Methods for treating subjects with Prader-Willi syndrome or Smith-Magenis syndrome

ABSTRACT

Provided are immediate or prolonged administration of certain potassium ATP (KATP) channel openers, optionally in combination with growth hormone, to a subject to achieve novel pharmacodynamic, pharmacokinetic, therapeutic, physiological, metabolic and compositional outcomes in the treatment of diseases or conditions involving KATP channels. Also provided are pharmaceutical formulations, methods of administration and dosing of KATP channel openers that achieve these outcomes and reduce the incidence of adverse effects in treated individuals. Further provided are methods of co-administering KATP channel openers with other drugs (e.g., in combination with growth hormone) to treat diseases of humans and animals (e.g., Prader-Willi Syndrome (PWS), Smith-Magenis syndrome (SMS), and the like.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.16/041,237, filed Jul. 20, 2018, which is a continuation of U.S. patentapplication Ser. No. 15/671,792, filed Aug. 8, 2017, now U.S. Pat. No.10,058,557, which is a divisional of U.S. patent application Ser. No.14/940,018, filed Nov. 12, 2015, now U.S. Pat. No. 9,757,384, whichclaims priority to U.S. Provisional Patent Application No. 62/080,150,filed Nov. 14, 2014, U.S. Provisional Patent Application No. 62/138,245,filed Mar. 25, 2015, U.S. Provisional Patent Application No. 62/170,035,filed Jun. 2, 2015, and U.S. Provisional Patent Application No.62/221,359, filed Sep. 21, 2015, each of which is incorporated herein inits entirety.

FIELD OF THE INVENTION

The present invention relates to pharmaceutical formulations ofpotassium ATP (K_(ATP)) channel openers and their use for treatment ofvarious diseases and conditions such as Prader-Willi Syndrome (PWS),Smith-Magenis syndrome (SMS), and the like.

BACKGROUND OF THE INVENTION

The following description of the background of the invention is providedsimply as an aid in understanding the invention and is not admitted todescribe or constitute prior art to the invention.

ATP-sensitive potassium (K_(ATP)) channels play important roles in avariety of tissues by coupling cellular metabolism to electricalactivity. The K_(ATP) channel has been identified as an octamericcomplex of two unrelated proteins, which assemble in a 4:4stoichiometry. The first is a pore forming subunit, Kir6.x, which formsan inwardly rectifying K⁺ channel; the second is an ABC (ATP bindingcassette) transporter, also known as the sulfonylurea receptor (SURx)(Babenko, et al., Annu. Rev. Physiol., 60:667-687 (1998)). The Kir6.xpore forming subunit is common for many types of K_(ATP) channels, andhas two putative transmembrane domains (identified as TM1 and TM2),which are linked by a pore loop (H5). The subunit that comprises the SURreceptor includes multiple membrane-spanning domains and twonucleotide-binding folds.

According to their tissue localization, K_(ATP) channels exist indifferent isoforms or subspecies resulting from the assembly of the SURand Kir subunits in multiple combinations. The combination of the SUR1with the Kir6.2 subunits (SUR1/Kir6.2) typically forms the adipocyte andpancreatic B-cell type K_(ATP) channels, whereas the SUR2A/Kir6.2 andthe SUR2B/Kir6.2 or Kir6.1 combinations typically form the cardiac typeand the smooth muscle type K_(ATP) channels, respectively (Babenko, etal., Annu. Rev. Physiol., 60:667-687 (1998)). There is also evidencethat the channel may include Kir2.x subunits. This class of potassiumchannels are inhibited by intracellular ATP and activated byintracellular nucleoside diphosphates. Such K_(ATP) channels link themetabolic status of the cells to the plasma membrane potential and inthis way play a key role in regulating cellular activity. In mostexcitatory cells, K_(ATP) channels are closed under normal physiologicalconditions and open when the tissue is metabolically compromised (e.g.when the (ATP:ADP) ratio falls). This promotes K+ efflux and cellhyperpolarization, thereby preventing voltage-operated Ca2+ channels(VOCs) from opening. (Prog Res Research, (2001) 31:77-80).

Potassium channel openers (PCOs or KCOs) (also referred to as channelactivators or channel agonists), are a structurally diverse group ofcompounds with no apparent common pharmacophore linking their ability toantagonize the inhibition of K_(ATP) channels by intracellularnucleotides. Diazoxide is a PCO that stimulates K_(ATP) channels inpancreatic β-cells (see Trube, et al., Pfluegers Arch kEur J Physiol,407, 493-99 (1986)). Pinacidil and chromakalim are PCOs that activatesarcolemmal potassium channels (see Escande, et al., Biochem Biophys ResCommun, 154, 620-625 (1988); Babenko, et al., J Biol Chem, 275(2),717-720 (2000)). Responsiveness to diazoxide has been shown to reside inthe 6^(th) through 11^(th) predicted transmembrane domains (TMD6-11) andthe first nucleotide-binding fold (NBF1) of the SUR1 subunit.

Diazoxide, which is a nondiuretic benzothiadiazine derivative having theformula 7-chloro-3-methyl-2H-1,2,4-benzothiadiazine 1.1-dioxide(empirical formula C₈H₇ClN₂O₂S), is commercialized in three distinctformulations to treat two different disease indications: 1) hypertensiveemergencies and 2) hyperinsulinemic hypoglycemic conditions.Hypertensive emergencies are treated with Hyperstat IV, an aqueousformulation of diazoxide for intravenous use, adjusted to pH 11.6 withsodium hydroxide. Hyperstat IV is administered as a bolus dose into aperipheral vein to treat malignant hypertension or sulfonylureaoverdose. In this use, diazoxide acts to open potassium channels invascular smooth muscle, stabilizing the membrane potential at theresting level, and preventing vascular smooth muscle contraction.

Hyperinsulinemic hypoglycemic conditions are treated with Proglycem, anoral pharmaceutical version of diazoxide useful for administration toinfants, children and adults. It is available as a chocolate mintflavored oral suspension, which includes 7.25% alcohol, sorbitol,chocolate cream flavor, propylene glycol, magnesium aluminum silicate,carboxymethylcellulose sodium, mint flavor, sodium benzoate,methylparaben, hydrochloric acid to adjust the pH, poloxamer 188,propylparaben and water. Diazoxide is also available as a capsule with50 or 100 mg of diazoxide including lactose and magnesium stearate.

Several experimental formulations of diazoxide have been tested inhumans and animals. These include an oral solution tested inpharmacodynamic and pharmacokinetic studies and a tablet formulationunder development as an anti-hypertensive, but never commercialized (seeCalesnick, et al., J. Pharm. Sci. 54:1277-1280 (1965); Reddy, et al.,AAPS Pharm Sci Tech 4(4):1-98, 9 (2003); U.S. Pat. No. 6,361,795).

Current oral formulations of diazoxide are labeled for dosing two orthree times per day at 8 or 12 hour intervals. Most patients receivingdiazoxide are dosed three times per day. Commercial and experimentalformulations of diazoxide are characterized by rapid drug releasefollowing ingestion with completion of release in approximately 2 hours.

Current oral formulations of diazoxide in therapeutic use result in arange of adverse side effects including dyspepsia, nausea, diarrhea,fluid retention, edema, reduced rates of excretion of sodium, chloride,and uric acid, hyperglycemia, vomiting, abdominal pain, ileus,tachycardia, palpitations, and headache (see current packaging insertfor the Proglycem). Oral treatment with diazoxide is used in individualsexperiencing serious disease where failing to treat results insignificant morbidity and mortality. The adverse side effects from oraladministration are tolerated because the benefits of treatment aresubstantial. The adverse side effects profile of oral diazoxide limitthe utility of the drug in treating obese patients at doses within thelabeled range of 3 to 8 mg/kg per day.

The effect of diazoxide in animal models of diabetes and obesity (e.g.obese and lean Zucker rats) has been reported. See e.g. Alemzadeh et al.(Endocrinology 133:705-712 (1993), Alemzadeh et al. (Metabolism45:334-341 (1996)), Alemzadeh et al. (Endocrinology 140:3197-3202(1999)), Stanridge et al. (FASEB J 14:455-460 (2000)), Alemzadeh et al.(Med Sci Monit 10(3): BR53-60 (2004)), Alemzadeh and Tushaus(Endocrinology 145(12):3476-3484 (2004)), Aizawa et al. (J of Pharma ExpTher 275(1): 194-199 (1995)), and Surwit et al. (Endocrinology141:3630-3637 (2000)).

The effect of diazoxide in humans with obesity or diabetes has beenreported. See e.g., Wigand and Blackard (Diabetes 28(4):287-291 (1979);evaluation of diazoxide on insulin receptors), Ratzmann et al. (Int JObesity 7(5):453-458 (1983); glucose tolerance and insulin sensitivityin moderately obese patients), Marugo et al. (Boll Spec It Biol Sper53:1860-1866 (1977); moderate dose diazoxide treatment on weight loss inobese patients), Alemzadeh et al. (J Clin Endocr Metab 83:1911-1915(1998); low dose diazoxide treatment on weight loss in obesehyperinsulinemic patients), Guldstrand et al. (Diabetes and Metabolism28:448-456 (2002); diazoxide in obese type II diabetic patients),Ortqvist et al. (Diabetes Care 27(9):2191-2197 (2004); beta-cellfunction measured by circulating C-peptide in children at clinical onsetof type 1 diabetes), Bjork et al. (Diabetes Care 21(3):427-430 (1998);effect of diazoxide on residual insulin secretion in adult type Idiabetes patients), and Qvigstad et al., (Diabetic Medicine 21:73-76(2004)).

U.S. Pat. No. 5,284,845 describes a method for normalizing blood glucoseand insulin levels in an individual exhibiting normal fasting bloodglucose and insulin levels and exhibiting in an oral glucose tolerancetest, elevated glucose levels and at least one insulin level abnormalityselected from the group consisting of a delayed insulin peak, anexaggerated insulin peak and a secondary elevated insulin peak.According to this reference, the method includes administering diazoxidein an amount from about 0.4 to about 0.8 mg/kg body weight before eachmeal in an amount effective to normalize the blood glucose and insulinlevels.

U.S. Pat. No. 6,197,765 describes administration of diazoxide as atreatment for syndrome-X, and resulting complications, that includehyperlipidemia, hypertension, central obesity, hyperinsulinemia andimpaired glucose intolerance. According to this reference, diazoxideinterferes with pancreatic islet function by ablating endogenous insulinsecretion resulting in a state of insulin deficiency and high bloodglucose levels equivalent to that of diabetic patients that depend onexogenous insulin administration for normalization of their bloodglucose levels.

U.S. Pat. No. 2,986,573 describes diazoxide and alkali metal salts forthe treatment of hypertension.

U.S. Pat. No. 5,629,045 describes diazoxide for topical ophthalmicadministration.

WO 98/10786 describes use of diazoxide in the treatment of X-syndromeincluding obesity associated therewith.

U.S. Patent publication no. 2003/0035106 describes diazoxide-containingcompounds for reducing the consumption of fat-containing foods.

U.S. Patent publication no. 2004/0204472 describes the use of a Cox-2inhibitor plus diazoxide in the treatment of obesity.

U.S. Patent publication no. 2002/0035106 describes the use of K_(ATP)channel openers including diazoxide and metal salts for reducing theconsumption of fat containing food.

SUMMARY OF THE INVENTION

Provided herein are pharmaceutical formulations of K_(ATP) channelopeners and their use (optionally in combination with growth hormone)for treatment of various diseases and conditions, including Prader-WilliSyndrome (PWS), Smith-Magenis syndrome (SMS), and the like. Suchformulations are characterized as being bioavailable. A K_(ATP) channelopener as used herein has any one or more of the following properties:(1) opening SUR1/Kir6.2 potassium channels; (2) binding to the SUR1subunit of K_(ATP) channels; and (3) inhibiting glucose induced releaseof insulin following administration of the compound in vivo. Preferably,K_(ATP) channel openers are K_(ATP) channel openers with all threeproperties. K_(ATP) channel openers as defined above preferably have thestructure of compounds of Formulas I-VII as set forth below.

In accordance with one aspect of the present invention, it has beendiscovered that one or more K_(ATP) channel opener(s) (optionally incombination with growth hormone) is effective for the treatment of asubject having Prader-Willi Syndrome (PWS), Smith-Magenis syndrome(SMS), and the like, and is especially effective for increasing the leanbody mass of such subjects. Therefore, in one aspect of the presentinvention, there are provided methods of increasing the lean body massof a subject having Prader-Willi Syndrome (PWS), Smith-Magenis syndrome(SMS), and the like, said method comprising administering to saidsubject for at least 4 weeks an effective amount of a K_(ATP) channelopener (optionally in combination with growth hormone).

In some embodiments, the lean body mass of said subject is increased byat least 1%. In some embodiments, the lean body mass of said subject isincreased by at least 2%. In some embodiments, the lean body mass ofsaid subject is increased by at least 3%. In some embodiments, the leanbody mass of said subject is increased by at least 4%. In someembodiments, the lean body mass of said subject is increased by at least5%.

In addition to increasing the lean body mass of a subject, in someembodiments, invention methods also reduce the hyperphagia of a subject.In some embodiments, the hyperphagia of said subject is reduced by atleast 10%. In some embodiments, the hyperphagia of said subject isreduced by at least 20%. In some embodiments, the hyperphagia of saidsubject is reduced by at least 30%.

In addition to increasing the lean body mass of a subject, in someembodiments, invention methods also reduce the body fat of a subject. Insome embodiments, the body fat of said subject is reduced by at least1%. In some embodiments, the body fat of said subject is reduced by atleast 3%. In some embodiments, the body fat of said subject is reducedby at least 5%.

In another aspect, the present invention provides a method of increasingthe lean body mass of a subject having Prader-Willi Syndrome (PWS),Smith-Magenis syndrome (SMS), and the like, wherein said subject isalready being treated by administration thereto of growth hormone, saidmethod comprising co-administering to said subject an effective amountof a K_(ATP) channel opener in addition to said growth hormone.

In yet another aspect, the present invention provides a method ofincreasing the lean body mass of a subject having Prader-Willi Syndrome(PWS), Smith-Magenis syndrome (SMS), and the like, wherein said subjectis already being treated by administration thereto of an effectiveamount of a K_(ATP) channel opener, said method comprisingco-administering to said subject an effective amount of growth hormonein addition to said K_(ATP) channel opener.

K_(ATP) channel openers defined by Formula I are as follows:

wherein:

-   -   R^(1a) and R^(1b), when present, are independently selected from        the group consisting of hydrogen, lower alkyl, substituted lower        alkyl, cycloalkyl, substituted cycloalkyl, amino, and        substituted amino;    -   R^(2a) and R^(2b), when present, are independently selected from        the group consisting of hydrogen, and lower alkyl;    -   X is a 1, 2 or 3 atom chain, wherein each atom is independently        selected from carbon, sulfur or nitrogen, and each atom is        optionally substituted with halogen, hydroxyl, lower alkyl,        substituted lower alkyl, lower alkoxy, cycloalkyl, substituted        cycloalkyl, substituted lower alkoxy, amino, or substituted        amino;    -   wherein rings A and B are each independently saturated,        monounsaturated, polyunsaturated or aromatic;    -   and all bioequivalents including salts, prodrugs and isomers        thereof.

In particular embodiments, compounds of Formula I may include a doublebond between either positions 1 and 2 or positions 2 and 3 of Ring A.When a double bond is present between positions 1 and 2 of Ring A,R^(2a) is absent and one of R^(1a) and R^(1b) are absent. When a doublebond is present between positions 2 and 3 of Ring A, R^(2b) is absentand one of R^(1a) and R^(1b) are absent. In a preferred embodiment,R^(1a) and R^(1b) are not amino. In another preferred embodiment, Ring Bdoes not include any heteroatoms.

K_(ATP) channel openers defined by Formula II being a subgenera ofFormula I are as follows:

wherein:

-   -   R¹ is selected from the group consisting of hydrogen, lower        alkyl, substituted lower alkyl, cycloalkyl, substituted        cycloalkyl, amino, and substituted amino;    -   R^(2a) is selected from the group consisting of hydrogen, and        lower alkyl;    -   X is a 1, 2 or 3 atom chain, wherein each atom is independently        selected from carbon, sulfur or nitrogen, and each atom is        optionally substituted with halogen, hydroxyl, lower alkyl,        substituted lower alkyl, lower alkoxy, cycloalkyl, substituted        cycloalkyl, substituted lower alkoxy, amino, or substituted        amino;    -   wherein ring B is saturated, monounsaturated, polyunsaturated or        aromatic;    -   and all bioequivalents including salts, prodrugs and isomers        thereof.

In particular embodiments of Formula II, X is C(R^(a))C(R^(b)), whereinR^(a) and R^(b) are independently selected from the group consisting ofhydrogen, halogen, lower alkyl, substituted lower alkyl, cycloalkyl,substituted cycloalkyl, lower alkoxy, substituted lower alkoxy, amino,sulfonylamino, aminosulfonyl, sulfonyl, and the like. In furtherembodiments, R^(a) and R^(b) are independently selected from the groupconsisting of hydroxyl, substituted oxy, substituted thiol, alkylthio,substituted alkylthio, sulfinyl, sulfonyl, substituted sulfinyl,substituted sulfonyl, substituted sulfonylamino, substituted amino,substituted amine, alkylsulfinyl, alkylsulfonyl, alkylsulfonylamino, andthe like. In a preferred embodiment, R¹ is not amino. In anotherpreferred embodiment, Ring B does not include any heteroatoms.

K_(ATP) channel openers defined by Formula III being a subgenera ofFormula I are as follows:

wherein:

-   -   R¹ is selected from the group consisting of hydrogen, lower        alkyl, substituted lower alkyl, cycloalkyl, substituted        cycloalkyl, amino, and substituted amino;    -   R^(2b) is selected from the group consisting of hydrogen, and        lower alkyl;    -   X is a 1, 2 or 3 atom chain, wherein each atom is independently        selected from carbon, sulfur or nitrogen, and each atom is        optionally substituted with halogen, hydroxyl, lower alkyl,        substituted lower alkyl, lower alkoxy, cycloalkyl, substituted        cycloalkyl, substituted lower alkoxy, amino, or substituted        amino;    -   wherein ring B is saturated, monounsaturated, polyunsaturated or        aromatic;    -   and all bioequivalents including salts, prodrugs and isomers        thereof.

In particular embodiments of Formula III, X is C(R^(a))C(R^(b)), whereinR^(a) and R^(b) are independently selected from the group consisting ofhydrogen, halogen, lower alkyl, substituted lower alkyl, cycloalkyl,substituted cycloalkyl, lower alkoxy, substituted lower alkoxy, amino,sulfonylamino, aminosulfonyl, sulfonyl, and the like. In furtherembodiments, R^(a) and R^(b) are independently selected from the groupconsisting of hydroxyl, substituted oxy, substituted thiol, alkylthio,substituted alkylthio, sulfinyl, sulfonyl, substituted sulfinyl,substituted sulfonyl, substituted sulfonylamino, substituted amino,substituted amine, alkylsulfinyl, alkylsulfonyl, alkylsulfonylamino, andthe like. In a preferred embodiment, R¹ is not amino. In anotherpreferred embodiment, Ring B does not include any heteroatoms.

K_(ATP) channel openers defined by Formula IV being a subgenera ofFormula I are as follows:

wherein:

-   -   R¹ is selected from the group consisting of hydrogen, lower        alkyl, substituted lower alkyl, cycloalkyl, amino, and        substituted lower amino;    -   R^(2a) is selected from the group consisting of hydrogen, lower        alkyl, and substituted lower alkyl;    -   R³ is selected from the group consisting of hydrogen, halogen,        lower alkyl, substituted lower alkyl, amino, and substituted        amino;    -   R⁴ is selected from the group consisting of hydrogen, halogen,        lower alkyl, substituted lower alkyl, amino, and substituted        amino;    -   and all bioequivalents including salts, prodrugs and isomers        thereof.

In particular embodiments of Formula IV, R¹ is a lower alkyl (preferablyethyl or methyl); R^(2a) is hydrogen; and R³ and R⁴ are eachindependently halogen.

In a preferred embodiment of Formula IV, R¹ is not amino.

In another embodiment of Formula IV, R¹ is methyl; R^(2a) is hydrogen;R³ is selected from the group consisting of hydrogen, halogen, loweralkyl, substituted lower alkyl, amino, substituted amino, cycloalkyl,and substituted cycloalkyl; and R⁴ is chlorine.

K_(ATP) channel openers defined by Formula V being a subgenera ofFormula I are as follows:

wherein:

-   -   R¹ is selected from the group consisting of hydrogen, lower        alkyl, substituted lower alkyl, cycloalkyl, amino, and        substituted lower amino;    -   R^(2b) is selected from the group consisting of hydrogen, lower        alkyl, and substituted lower alkyl;    -   R³ is selected from the group consisting of hydrogen, halogen,        lower alkyl, substituted lower alkyl, amino, and substituted        amino;    -   R⁴ is selected from the group consisting of hydrogen, halogen,        lower alkyl, substituted lower alkyl, amino, and substituted        amino;    -   and all bioequivalents including salts, prodrugs and isomers        thereof.

In particular embodiments of Formula V, R¹ is a lower alkyl (preferablyethyl or methyl); R^(2b) is hydrogen; and R³ and R⁴ are eachindependently halogen.

In a preferred embodiment of Formula V, R¹ is not amino.

In another embodiment of Formula V, R¹ is methyl; R^(2b) is hydrogen; R³is selected from the group consisting of hydrogen, halogen, lower alkyl,substituted lower alkyl, amino, substituted amino, cycloalkyl, andsubstituted cycloalkyl; and R⁴ is chlorine.

K_(ATP) channel openers defined by Formula VI are as follows:

wherein:

-   -   R¹ is selected from the group consisting of hydrogen, lower        alkyl, substituted lower alkyl, cycloalkyl, substituted        cycloalkyl, amino, and substituted lower amino, or R¹ can        cooperate with R⁵ or R⁶ to form an additional ring;    -   R^(2a) is selected from the group consisting of hydrogen, lower        alkyl, and substituted lower alkyl;    -   R⁵ is selected from the group consisting of hydrogen, halogen,        hydroxyl, lower alkyl, substituted lower alkyl, amino,        substituted amino, sulfonyl, aminosulfonyl, and sulfonylamino,        or R⁵ can cooperate with R¹ or R⁶ to form an additional ring;    -   R⁶ is selected from the group consisting of hydrogen, halogen,        lower alkyl, substituted lower alkyl, amino, substituted amino,        sulfonyl, aminosulfonyl, and sulfonylamino, or R⁶ can cooperate        with R¹ or R⁵ to form an additional ring;    -   wherein the ring formed by the cooperation of R¹ and R⁵, or R¹        and R⁶, or R⁵ and R⁶ is saturated, monounsaturated,        polyunsaturated or aromatic;    -   wherein the ring formed by the cooperation of R¹ and R⁵, or R¹        and R⁶, or R⁵ and R⁶ is optionally substituted with halogen,        hydroxyl, lower alkyl, substituted lower alkyl, amino,        substituted amino, sulfonyl, aminosulfonyl, or sulfonylamino;    -   and all bioequivalents including salts, prodrugs and isomers        thereof.

In a preferred embodiment, R¹ is not an amino substituent.

In another embodiment of Formula VI, R⁵ and R⁶ combine to form a 6membered ring. In another embodiment, R⁵ and R⁶ combine to form a 6membered ring wherein at least one nitrogen is present. Preferably, thering formed by R⁵ and R⁶ does not include any heteroatoms.

K_(ATP) channel openers defined by Formula VII are as follows:

wherein:

-   -   R¹ is selected from the group consisting of hydrogen, lower        alkyl, substituted lower alkyl, cycloalkyl, substituted        cycloalkyl, amino, and substituted lower amino, or R¹ can        cooperate with R⁵ or R⁶ to form an additional ring;    -   R^(2b) is selected from the group consisting of hydrogen, lower        alkyl, and substituted lower alkyl;    -   R⁵ is selected from the group consisting of hydrogen, halogen,        hydroxyl, lower alkyl, substituted lower alkyl, amino,        substituted amino, sulfonyl, aminosulfonyl, and sulfonylamino,        or R⁵ can cooperate with R¹ or R⁶ to form an additional ring;    -   R⁶ is selected from the group consisting of hydrogen, halogen,        lower alkyl, substituted lower alkyl, amino, substituted amino,        sulfonyl, aminosulfonyl, and sulfonylamino, or R⁶ can cooperate        with R¹ or R⁵ to form an additional ring;    -   wherein the ring formed by the cooperation of R¹ and R⁵, or R¹        and R⁶, or R⁵ and R⁶ is saturated, monounsaturated,        polyunsaturated or aromatic;    -   wherein the ring formed by the cooperation of R¹ and R⁵, or R¹        and R⁶, or R⁵ and R⁶ is optionally substituted with halogen,        hydroxyl, lower alkyl, substituted lower alkyl, amino,        substituted amino, sulfonyl, aminosulfonyl, or sulfonylamino;    -   and all bioequivalents including salts, prodrugs and isomers        thereof.

In a preferred embodiment, R¹ is not an amino substituent.

In another embodiment of Formula VI, R⁵ and R⁶ combine to form a 6membered ring. In another embodiment, R⁵ and R⁶ combine to form a 6membered ring wherein at least one nitrogen is present. Preferably, thering formed by R⁵ and R⁶ does not include any heteroatoms.

Unless otherwise indicated, reference in this application to K_(ATP)channel openers should be understood to refer to K_(ATP) channelopener(s) having one or more and preferably all three of the followingproperties: (1) opening SUR1/Kir6.2 potassium channels; (2) binding tothe SUR1 subunit of K_(ATP) channels; and (3) inhibiting glucose inducedrelease of insulin following administration of the compound in vivo.Such K_(ATP) channel openers preferably have the structure of any of thecompounds of Formulae I-VII, or more preferably Formulae I-VII where R¹is not amino and also where ring B or its equivalent does not includeany heteroatoms, or more preferably, any of the compounds of Formulae IIor III, or more preferably, any of the compounds of Formulae II or IIIwhere R¹ is not amino and also where ring B or its equivalent does notinclude any heteroatoms, or more preferably, the structure is diazoxide.Structural variants or bioequivalents of the compounds of any ofFormulae I-VII such as derivatives, salts, prodrugs or isomers are alsocontemplated. Other K_(ATP) channel openers that are contemplated foruse herein include BPDZ62, BPDZ 73, NN414, BPDZ 154.

In vitro analysis of glucose induced release of insulin via K_(ATP)channel openers can be determined using rat islets as provided by DeTullio, et al., J. Med. Chem., 46:3342-3353 (2003) or by using humanislets as provided by Björklund, et al., Diabetes, 49:1840-1848 (2000).

Provided herein are formulations, such as controlled releasepharmaceutical formulations, of K_(ATP) channel openers andbioequivalents thereof. In one embodiment, the controlled releaseformulations are formulated for oral administration. Such formulationscontain in a single administration dosage between 10 and 100 mg, between25 and 100 mg, between 100 and 200 mg, between 200 and 300 mg, between300 and 500 mg or between 500 and 2000 mg of the K_(ATP) channelopeners. In certain embodiments, the dosage of the K_(ATP) channelopeners contained in a formulation may be determined based on the weightof the patient for which it is to be administered, i.e., the formulationmay contain in a single administration dosage between 0.1-20 mg of theK_(ATP) channel opener per kg of the patient's body weight, or between0.1-0.5 mg of the K_(ATP) channel opener per kg of the patient's bodyweight; or between 0.5-1 mg of the K_(ATP) channel opener per kg of thepatient's body weight; or between 1-2 mg of the K_(ATP) channel openerper kg of the patient's body weight, or between 2-5 mg of the K_(ATP)channel opener per kg of the patient's body weight, or between 5-10 mgof the K_(ATP) channel opener per kg of the patient's body weight, orbetween 10-15 mg of the K_(ATP) channel opener per kg of the patient'sbody weight, or between 15-20 mg of the K_(ATP) channel opener per kg ofthe patient's body weight.

Also provided herein are controlled release pharmaceutical formulationscontaining K_(ATP) channel openers obtained by at least one of thefollowing: (a) particle size reduction involving comminution, spraydrying, or other micronising techniques, (b) use of a pharmaceuticalsalt of the K_(ATP) channel opener, (c) use of an ion exchange resin,(d) use of inclusion complexes, for example cyclodextrin, (e) compactionof the K_(ATP) channel opener with a solubilizing agent including a lowviscosity hypromellose, low viscosity methylcellulose or similarlyfunctioning excipient or combinations thereof, (f) associating theK_(ATP) channel opener with a salt prior to formulation, (g) use of asolid dispersion of the K_(ATP) channel opener, (h) use of a selfemulsifying system, (i) addition of one or more surfactants to theformulation, (j) use of nanoparticles, or (k) combinations of theseapproaches.

Further provided herein are controlled release pharmaceuticalformulations containing K_(ATP) channel openers which include at leastone component that substantially inhibits release of the K_(ATP) channelactivator from the formulation until after gastric transit. As usedherein, “substantially inhibits” means less than 15% release, morepreferably at least less than 10% release, or more preferably at leastless than 5% release of the drug from the formulation during gastrictransport. Release can be measured in a standard USP based in-vitrogastric dissolution assay in a calibrated dissolution apparatus (see,for example, U.S. Pharmacopeia, Chapter 711 (2005)).

Also provided are oral pharmaceutical formulations of K_(ATP) channelopeners which include at least one component that substantially inhibitsrelease of the K_(ATP) channel opener from the formulation until aftergastric transit. Substantial inhibition of drug release during gastrictransit is achieved by inclusion of a component in the formulationselected from the group consisting of: (a) a pH sensitive polymer orco-polymer applied as a compression coating on a tablet, (b) a pHsensitive polymer or co-polymer applied as a thin film on a tablet, (c)a pH sensitive polymer or co-polymer applied as a thin film to anencapsulation system, (d) a pH sensitive polymer or co-polymer appliedto encapsulated microparticles, (e) a non-aqueous-soluble polymer orco-polymer applied as a compression coating on a tablet, (f) anon-aqueous-soluble polymer or co-polymer applied as a thin film on atablet, (g) a non-aqueous soluble polymer applied as a thin film to anencapsulation system, (h) a non-aqueous soluble polymer applied tomicroparticles, (i) incorporation of the formulation in an osmotic pumpsystem, (j) use of systems controlled by ion exchange resins, and (k)combinations of these approaches, wherein the pH sensitive polymer orco-polymer is resistant to degradation under acid conditions.

Also provided herein are controlled release pharmaceutical formulationsof K_(ATP) channel openers, wherein the formulation includes at leastone component that contributes to sustained release of a K_(ATP) channelopener over a period of 2-4 hours following administration, or over aperiod of 4-8 hours following administration, or over a period of morethan 8-24 hours following administration. These formulations arecharacterized in having one of the following components: (a) a pHsensitive polymeric coating, (b) a hydrogel coating, (c) a film coatingthat controls the rate of diffusion of the drug from a coated matrix,(d) an erodable matrix that controls rate of drug release, (e) polymercoated pellets, granules or microparticles of drug which can be furtherencapsulated or compressed into a tablet, (f) an osmotic pump systemcontaining the drug, (g) a compression coated tablet form of the drug,or (h) combinations of these approaches.

As used herein, an erodable matrix is the core of a tablet formulationthat, upon exposure to an aqueous environment, begins a process ofdisintegration which facilitates the release of drug from the matrix.The rate of release of drug from the tablet is controlled both by thesolubility of the drug and the rate of disintegration of the matrix.

The above formulations may further comprise one or more additionalpharmaceutically active agents (other than K_(ATP) channel openers)useful for the treatment of a condition selected from the groupconsisting of obesity, prediabetes, diabetes, hypertension, depression,elevated cholesterol, fluid retention, other obesity associatedcomorbidities, ischemic and reperfusion injury, epilepsy, schizophrenia,mania, or other psychotic diseases.

Further provided is a controlled release pharmaceutical formulation of aK_(ATP) channel opener wherein administration to an obese, overweight orobesity prone individual results in at least one of the following: (a)inhibition of fasting insulin secretion (b) inhibition of stimulatedinsulin secretion, (c) elevation of energy expenditure, (d) elevation ofbeta oxidation of fat, (e) inhibition of hyperphagia for about 24 hours,or (f) increase in lean body mass.

Additionally provided is a controlled release pharmaceutical formulationof a K_(ATP) channel opener wherein administration to an obese,overweight or obesity prone individual results in at least one of thefollowing: (a) inhibition of fasting insulin secretion (b) inhibition ofglucose stimulated insulin secretion, (c) elevation of energyexpenditure, (d) elevation of beta oxidation of fat, (e) inhibition ofhyperphagia for about 18 hours, or (f) increase in lean body mass.

Still further provided is a controlled release pharmaceuticalformulation of a K_(ATP) channel opener which upon administration to anobese, overweight or obesity prone individual results in at least one ofthe following: (a) inhibition of fasting insulin secretion (b)inhibition of glucose stimulated insulin secretion, (c) elevation ofenergy expenditure, (d) elevation of beta oxidation of fat, (e)inhibition of hyperphagia for about 24 hours, or (f) increase in leanbody mass.

Additionally provided is a controlled release pharmaceutical formulationof a K_(ATP) channel opener that upon administration to an obese,overweight or obesity prone individual results in at least one of thefollowing: (a) inhibition of fasting insulin secretion (b) inhibition ofglucose stimulated insulin secretion, (c) elevation of energyexpenditure, (d) elevation of beta oxidation of fat, (e) inhibition ofhyperphagia for about 18 hours, or (f) increase in lean body mass.

Provided herein is a method of treating hypoglycemia, the methodcomprising orally administering a controlled release formulation of aK_(ATP) channel opener, optionally in combination with growth hormone.

Further provided herein is a method of treating obesity associatedco-morbidities in an obese, overweight or obesity prone individual, themethod comprising administering a therapeutically effective amount of asolid oral dosage form of a K_(ATP) channel opener, or controlledrelease pharmaceutical formulation of a K_(ATP) channel opener,optionally in combination with growth hormone. In a preferredembodiment, administration is no more than two times per 24 hours, oronce per 24 hours.

Yet further provided herein is a method of achieving weight loss in anobese overweight, or obesity prone individual, the method comprisingadministering a therapeutically effective amount of a solid oral dosageform of a K_(ATP) channel opener or controlled release pharmaceuticalformulation of a K_(ATP) channel opener, optionally in combination withgrowth hormone. In a preferred embodiment, administration is no morethan two times per 24 hours, or once per 24 hours. The daily dosageadministered is preferably between 50 and 180 mg. In certainembodiments, the obese individual has a body mass index greater than 30kg/m², or greater than 35 kg/m², or greater than 40 kg/m², or greaterthan 50 kg/m², or greater than 60 kg/m² at the time the methodcommences.

Also provided is a method of maintaining a weight loss in an obeseoverweight, or obesity prone individual, the method comprisingadministering a therapeutically effective amount of a solid oral dosageform of a K_(ATP) channel opener or controlled release pharmaceuticalformulation of a K_(ATP) channel opener, optionally in combination withgrowth hormone. It is preferable to maintain weight in an obeseindividual once some weight loss has occurred when the alternative is toregain weight. In a preferred embodiment, administration is no more thantwo times per 24 hours, or once per 24 hours.

Further provided is a method of elevating energy expenditure in anoverweight, obese or obesity prone individual, the method comprisingadministering an effective amount of a solid oral dosage form of aK_(ATP) channel opener or controlled release pharmaceutical formulationof a K_(ATP) channel opener, optionally in combination with growthhormone. In a preferred embodiment, administration is no more than twotimes per 24 hours, or once per 24 hours. In certain embodiments, theindividual has a body mass index greater than 20 kg/m², or greater than25 kg/m², or greater than 30 kg/m², or greater than 35 kg/m², or greaterthan 40 kg/m², or greater than 50 kg/m², or greater than 60 kg/m² at thetime the method commences.

Additionally provided is a method of elevating beta oxidation of fat inan overweight, obese or obesity prone individual, the method comprisingadministering an effective amount of a solid oral dosage form of aK_(ATP) channel opener or controlled release pharmaceutical formulationof a K_(ATP) channel opener, optionally in combination with growthhormone. In a preferred embodiment, administration is no more than twotimes per 24 hours, or once per 24 hours. In certain embodiments, theindividual has a body mass index greater than 20 kg/m², or greater than25 kg/m², or greater than 30 kg/m², or greater than 35 kg/m², or greaterthan 40 kg/m², or greater than 50 kg/m², or greater than 60 kg/m² at thetime the method commences.

Yet further provided is a method of reducing visceral fat in anoverweight, obese or obesity prone individual, the method comprisingadministering an effective amount of a solid oral dosage form of aK_(ATP) channel opener or controlled release pharmaceutical formulationof a K_(ATP) channel opener, optionally in combination with growthhormone. In a preferred embodiment, administration is no more than twotimes per 24 hours, or once per 24 hours.

Still further provided is a method of delaying or preventing thetransition to diabetes of a prediabetic individual comprisingadministering an effective amount of a K_(ATP) channel opener orcontrolled release pharmaceutical formulation of a K_(ATP) channelopener, optionally in combination with growth hormone. In a preferredembodiment, administration is no more than two times per 24 hours, oronce per 24 hours.

Additionally provided is a method of restoring normal glucose tolerancein a prediabetic individual comprising administering an effective amountof a K_(ATP) channel opener or controlled release pharmaceuticalformulation of a K_(ATP) channel opener, optionally in combination withgrowth hormone. In a preferred embodiment, administration is no morethan two times per 24 hours, or once per 24 hours.

Further provided is a method of restoring normal glucose tolerance in adiabetic individual comprising administering an effective amount of aK_(ATP) channel opener or controlled release pharmaceutical formulationof a K_(ATP) channel opener, optionally in combination with growthhormone. In a preferred embodiment, administration is no more than twotimes per 24 hours, or once per 24 hours.

Still further provided is a method of delaying or preventing progressionof diabetes in an individual comprising administering an effectiveamount of a K_(ATP) channel opener or controlled release pharmaceuticalformulation of a K_(ATP) channel opener, optionally in combination withgrowth hormone. In a preferred embodiment, administration is no morethan two times per 24 hours, or once per 24 hours.

Also provided is a method to prevent or treat weight gain, impairedglucose tolerance or dyslipidemia associated with the use ofanti-psychotics to treat patients comprising the co-administration of aneffective amount of a K_(ATP) channel opener or controlled releasepharmaceutical formulation of a K_(ATP) channel opener, optionally incombination with growth hormone. In a preferred embodiment,administration is no more than two times per 24 hours, or once per 24hours.

Further provided is a method to increase lean body mass in aPrader-Willi Syndrome patient, in a Smith-Magenis syndrome patient, in aFroelich's Syndrome patient, in a Cohen Syndrome patient, in a SummitSyndrome patient, in an Alstrom Syndrome patient, in a Borjeson Syndromepatient or in a Bardet-Biedl Syndrome patient comprising theadministration of an effective amount of a K_(ATP) channel opener(optionally in combination with growth hormone) or a controlled releasepharmaceutical formulation of a K_(ATP) channel opener (optionally incombination with growth hormone). In a preferred embodiment,administration is no more than two times per 24 hours, or once per 24hours.

Still further provided is a method to treat obesity or elevatedtriglycerides in a patient suffering hyperlipoproteinemia type I, typeII, type III or type IV comprising administering an effective amount ofa K_(ATP) channel opener or controlled release pharmaceuticalformulation of a K_(ATP) channel opener, optionally in combination withgrowth hormone. In a preferred embodiment, administration is no morethan two times per 24 hours, or once per 24 hours.

Also provided is a method of reducing the incidence of adverse effectsfrom administration of a K_(ATP) channel opener in the treatment ofdiseases of a subject achieved by any of the following: (a) use of adosage form that on administration reduces C_(max) relative to thecurrent Proglycem oral suspension or capsule products in order to reducethe incidence of adverse side effects that are associated with peak druglevels, (b) use of a dosage form that delays release until gastrictransit is complete in order to reduce the incidence of adverse sideeffects that are associated with the release of drug in the stomach, (c)initiating dosing at subtherapeutic levels and in a stepwise mannerincreasing dose daily until the therapeutic dose is achieved wherein thenumber of steps is 2 to 10 to reduce the incidence of adverse sideeffects that occur transiently at the initiation of treatment, (d) useof the lowest effective dose to achieve the desired therapeutic effectin order to reduce the incidence of adverse side effects that are dosedependent, or (e) optimizing the timing of administration of dose withinthe day and relative to meals.

Further provided is a method of preventing weight gain, dyslipidemia orimpaired glucose tolerance in a subject treated with an anti-psychoticdrug, the method comprising administering a pharmaceutical formulationof a K_(ATP) channel opener, optionally in combination with growthhormone.

Yet further provided is a method of treating weight gain, dyslipidemiaor impaired glucose tolerance in a subject treated with ananti-psychotic drug, the method comprising administering apharmaceutical formulation of a K_(ATP) channel opener, optionally incombination with growth hormone.

Also provided is a method of treating diseases characterized by obesity,hyperphagia, dyslipidemia, or decreased energy expenditure including (a)Prader Willi Syndrome, (b) Froelich's syndrome, (c) Cohen syndrome, (d)Summit Syndrome, (e) Alstrom, Syndrome, (f) Borjesen Syndrome, (g)Bardet-Biedl Syndrome, (h) hyperlipoproteinemia type I, II, III, and IV,or (i) Smith-Magenis syndrome (SMS), said method comprisingadministering a pharmaceutical formulation of a K_(ATP) channel opener,optionally in combination with growth hormone.

Further provided is a pharmaceutical formulation of a K_(ATP) channelopener further comprising a pharmaceutically active agent other than theK_(ATP) channel opener. In this formulation, the other pharmaceuticallyactive agent is an agent useful for the treatment of a conditionselected from the group consisting of obesity, prediabetes, diabetes,hypertension, depression, elevated cholesterol, fluid retention, orother obesity associated comorbidities, ischemic and reperfusion injury,epilepsy, schizophrenia, mania, and other psychotic condition.

The formulations containing K_(ATP) channel openers described hereinprovide for improved compliance, efficacy and safety, and forco-formulations with other agents. Included are co-formulations ofK_(ATP) channel openers with one or more additional pharmaceuticallyactive agents that have complementary or similar activities or targets.Other pharmaceutical active agents that can be combined with K_(ATP)channel openers to treat obesity or to maintain weight loss in anobesity prone individual include, but are not limited to: sibutramine,orlistat, phentermine, rimonabant, a diuretic, an antiepileptic, orother pharmaceutical active whose therapeutic utility includes weightloss. It is preferable to maintain weight in an obese individual oncesome weight loss has occurred when the alternative is to regain weight.Other pharmaceutically active agents that may be combined with K_(ATP)channel openers to treat type II diabetes, or prediabetes includeacarbose, miglitol, metformin, repaglinide, nateglinide, rosiglitizone,proglitizone, ramipril, metaglidasen, or any other pharmaceutical activethat improves insulin sensitivity or glucose utilization or glycemiccontrol where the mode of action is not enhanced insulin secretion.Other pharmaceutical active agents that can be combined with K_(ATP)channel openers to treat obesity associated co-morbidities include adrug active used to lower cholesterol, a drug active used to lower bloodpressure, an anti-inflammatory drug that is not a cox-2 inhibitor, adrug that is an antidepressant, a drug used to treat urinaryincontinence, or other drug routinely used to treat disease conditionsthe incidence of which is elevated in overweight or obese patients ascompared to normal weight individuals including, but not limited to,drugs to treat atherosclerosis, osteoarthritis, disc herniation,degeneration of knees and hips, breast, endometrium, cervical, colon,leukemia and prostate cancers, hyperlipidemia, asthma/reactive airwaydisease, gallstones, GERD, obstructive sleep apnea, obesityhypoventilation syndrome, recurrent ventral hernias, menstrualirregularity, infertility, and the like.

In the present context, the term “therapeutically effective” or“effective amount” indicates that the materials or amount of material iseffective to prevent, alleviate, or ameliorate one or more symptoms of adisease or medical condition, and/or to prolong the survival of thesubject being treated.

The term “pharmaceutically acceptable” indicates that the identifiedmaterial does not have properties that would cause a reasonably prudentmedical practitioner to avoid administration of the material to apatient, taking into consideration the disease or conditions to betreated and the respective route of administration. For example, it iscommonly required that such a material be essentially sterile, e.g., forinjectables.

As used herein, the term “composition” refers to a formulation suitablefor administration to an intended animal subject for therapeuticpurposes; exemplary formulations contain at least one pharmaceuticallyactive compound and at least one pharmaceutically acceptable carrier orexcipient. Other terms as used herein are defined below.

Adipocyte: An animal connective tissue cell specialized for thesynthesis and storage of fat.

Agonist: A chemical compound that has affinity for and stimulatesphysiological activity at cell receptors normally stimulated bynaturally occurring substances, triggering a biochemical response. Anagonist of a receptor can also be considered an activator of thereceptor.

About: is used herein to mean in quantitative terms plus or minus 10%.

Adipose tissue: Tissue comprised principally of adipocytes.

Adolescent: A person between 10 and 19 years of age.

Adiponectin: A protein hormone produced and secreted exclusively byadipocytes that regulates the metabolism of lipids and glucose.Adiponectin influences the body's response to insulin. Adiponectin alsohas anti-inflammatory effects on the cells lining the walls of bloodvessels.

Amelioration of the symptoms of a particular disorder by administrationof a particular pharmaceutical composition: refers to any lessening,whether permanent or temporary, lasting or transient that can beattributed to or associated with administration of the composition.

Analog: a compound that resembles another in structure but differs by atleast one atom.

Antagonist: A substance that tends to nullify the action of another, asa drug that binds to a cell receptor without eliciting a biologicalresponse.

Atherosclerotic Plaque: A buildup of cholesterol and fatty materialwithin a blood vessel due to the effects of atherosclerosis

Bariatric Surgery: a range of surgical procedures which are designed toaid in the management or treatment of obesity and allied diseases.

Beta cell rest: Temporarily placing beta cells in a condition in whichthere is reduced metabolic stress due to suppressed secretion ofinsulin.

Bilaminate: A component of a pharmaceutical dosage form that consists ofthe lamination of two distinct materials.

Bioavailability: Refers to the amount or extent of therapeuticallyactive substance that is released from the drug product and becomesavailable in the body at the intended site of drug action. The amount orextent of drug released can be established by thepharmacokinetic-parameters, such as the area under the blood or plasmadrug concentration-time curve (AUC) and the peak blood or plasmaconcentration (C_(max)) of the drug.

Bioequivalent: Two formulations of the same active substance arebioequivalent when there is no significant difference in the rate andextent to which the active substance becomes available at the site ofdrug action when administered at the same molar dose under similarconditions. “Formulation” in this definition may include the free baseof the active substance or different salts of the active substance.Bioequivalence may be demonstrated through several in vivo and in vitromethods. These methods, in descending order of preference, includepharmacokinetic, pharmacodynamic, clinical and in vitro studies. Inparticular, bioequivalence is demonstrated using pharmacokineticmeasures such as the area under the blood or plasma drugconcentration-time curve (AUC) and the peak blood or plasmaconcentration (Cmax) of the drug, using statistical criteria.

Cannabinoid Receptor: Receptors in the endocannabinoid (EC) systemassociated with the intake of food and tobacco dependency. Blocking thecannabinoid receptor may reduce dependence on tobacco and the cravingfor food.

Combination: refers to any association between or among two or moreitems. The combination can be two or more separate items, such as twocompositions or two collections. It can be a mixture thereof, such as asingle mixture of the two or more items, or any variation thereof.

Composition: refers to any mixture. It can be a solution, a suspension,liquid, powder, a paste, aqueous, non-aqueous or any combinationthereof.

Compression tablet: Tablet formed by the exertion of pressure to avolume of tablet matrix in a die.

Compression coated tablet: A tablet formed by the addition of a coatingby compression to a compressed core containing the pharmaceuticalactive.

Derivative: a chemical substance derived from another substance bymodification or substitution.

Daily dosage: the total amount of a drug taken in a 24 hour periodwhether taken as a single dose or taken in multiple doses.

Diazoxide: 7-chloro-3-methyl-2-H-1,2,4-benzothiadiazine 1,1 dioxide withthe empirical formula C₈H₇ClN₂O₂S and a molecular weight of 230.7.

Encapsulation system: a structural feature that contains drug withinsuch as a pharmaceutical capsule. A gel into which drug is incorporatedalso is considered an encapsulation system.

Equivalent amount: an amount of a derivative of a drug that in assays orupon administration to a subject produces an equal effect to a definedamount of the non-derivatized drug.

Fatty acid synthase: The central enzyme of a multienzyme complex thatcatalyses the formation of palmitate from acetylcoenzyme A,malonylcoenzyme A, and NADPH.

Gastric Lipase: An enzyme secreted into the gastrointestinal tract thatcatalyzes the hydrolysis of dietary triglycerides.

Glidant: An inactive component of a pharmaceutical formulation thatprevents caking of the matrix during processing steps.

Growth hormone: also known as somatotropin or somatropin, is a peptidehormone that stimulates growth, cell reproduction and regeneration inhumans and other animals. It is a type of mitogen which is specific onlyto certain kinds of cells. Growth hormone is a 191-amino acid,single-chain polypeptide that is synthesized, stored, and secreted bysomatotropic cells within the lateral wings of the anterior pituitarygland. GH is a stress hormone that raises the concentration of glucoseand free fatty acids. It also stimulates production of IGF-1.

Hyperinsulemia: Excessively high blood insulin levels, which isdifferentiated from hyperinsulinism, excessive secretion of insulin bythe pancreatic islets. Hyperinsulinemia may be the result of a varietyof conditions, such as obesity and pregnancy.

Hyperinsulinism: Excessive secretion of insulin by the pancreaticislets.

Hyperlipidemia: A general term for elevated concentrations of any or allof the lipids in the plasma, such as cholesterol, triglycerides andlipoproteins.

Hyperphagia: Ingestion of a greater than optimal quantity of food.

Ingredient of a pharmaceutical composition: refers to one or morematerials used in the manufacture of a pharmaceutical composition.Ingredient can refer to an active ingredient (an agent) or to othermaterials in the compositions. Ingredients can include water and othersolvents, salts, buffers, surfactants, water, non-aqueous solvents, andflavorings.

IGF-1, also called somatomedin C, is a protein that in humans is encodedby the IGF1 gene. IGF-1 is a hormone similar in molecular structure toinsulin. It plays an important role in childhood growth and continues tohave anabolic effects in adults. IGF-1 consists of 70 amino acids in asingle chain with three intramolecular disulfide bridges, and has amolecular weight of 7,649 daltons.

Insulin resistance: A condition in which the tissues of the body arediminished in their response to insulin.

Ischemic injury: injury to tissue that results from a low oxygen stateusually due to obstruction of the arterial blood supply or inadequateblood flow leading to hypoxia in the tissue.

Ketoacidosis: Acidosis accompanied by the accumulation of ketone bodies(ketosis) in the body tissue and fluids, as in diabetic acidosis.

Kit: refers to a packaged combination. A packaged combination canoptionally include a label or labels, instructions and/or reagents foruse with the combination.

Kir: Pore forming subunit of the K_(ATP) channel. Also known as theinwardly rectifying subunit of the K_(ATP) channel. Typically existingas Kir6.x and infrequently as Kir2.x subspecies.

K_(ATP) channel: An ATP sensitive potassium ion channel across the cellmembrane formed by the association of 4 copies of a sulfonylureareceptor and 4 copies of a pore forming subunit Kir. Agonizing thechannel can lead to membrane hyperpolarization.

Lean body mass: Lean Body Mass is a component of body composition,calculated by subtracting body fat weight from total body weight: totalbody weight is lean plus fat. In equations:Lean Body Mass equals Body Weight minus Body Fat (LBM=BW−BF)Lean Body Mass plus Body Fat equals Body Weight (LBM+BF=BW)The percentage of total body mass that is lean is usually not quoted—itwould typically be 60-90%. Instead, the body fat percentage, which isthe complement, is computed, and is typically 10-40%. The Lean body mass(LBM) has been described as an index superior to total body weight forprescribing proper levels of medications and for assessing metabolicdisorders, as body fat is less relevant for metabolism.

Leptin: Product (16 kD) of the ob (obesity) locus. It is found in plasmaof mammals and exerts a hormonal action, which reduces food uptake andincreases energy expenditure.

Lipogenesis: The generation of new lipids, primarily triacylglycerides.It is dependent on the action of multiple distinct enzymes and transportmolecules.

Lipolysis: The breakdown of fat by the coordinated action of multipleenzymes.

Lipoprotein lipase: An enzyme of the hydrolase class that catalyses thereaction of triacyglycerol and water to yield diacylglyerol and a fattyacid anion. The enzyme hydrolyses triacylglycerols in chylomicrons,very-low-density lipoproteins, low-density lipoproteins, anddiacylglycerols.

Lubricant: An inactive component of a pharmaceutical formulation thatprovides for the flow of materials in various processing steps,particularly tableting.

Microparticle: A small particulate formed in the process of developingpharmaceutical formulations that may be coated prior to producing thefinal dosage from.

Obesity: An increase in body weight beyond the limitation of skeletaland physical requirement, as the result of an excessive accumulation offat in the body. Formally defined as having a body mass index greaterthan 30 kg/m².

Obesity Prone: Individuals who because of genetic predisposition orprior history of obesity are at above average risk of becoming obese.

Obesity related co-morbidities: any disease or condition of animals orhumans that are increased incidence in obese or overweight individuals.Examples of such conditions include hypertension, prediabetes, type 2diabetes, osteoarthritis and cardiovascular conditions.

Osmotically controlled release: A pharmaceutical dosage form in whichthe release of the active drug is principally achieved by the hydrationof a swellable component of the formulation.

Overweight: an individual whose weight is above that which is ideal fortheir height but who fails to meet the criteria for classification asobese. In humans using Body Mass Index (kg/m²) an overweight individualhas a BMI between 25 and 30.

Oxidation of Fat: A series of reactions involving acyl-coenzyme Acompounds, whereby these undergo beta oxidation and thioclasticcleavage, with the formation of acetylcoenzyme A; the major pathway offatty acid catabolism in living tissue.

Pharmaceutical composition: refers a composition that contains an agentand one or more other ingredients that is formulated for administrationto a subject. An agent refers to an active ingredient of apharmaceutical composition. Typically active ingredients are active fortreatment of a disease or condition. For example, agents that can beincluded in pharmaceutical compositions include agents for treatingobesity or diabetes. The pharmaceutically active agent can be referredto as “a pharmaceutical active.”

Pharmaceutical effect: refers to an effect observed upon administrationof an agent intended for treatment of a disease or disorder or foramelioration of the symptoms thereof.

Pharmacodynamic: An effect mediated by drug action.

Pharmacokinetic: Relating to the absorption, distribution, metabolismand elimination of the drug in the body.

Polymorph: A compound that shares the same chemistry but a differentcrystal structure.

Prader-Willi syndrome (PWS): A complex neurobehavioral/metabolicdisorder which is due to the absence of normally active, paternallyexpressed genes from the chromosome 15q11-q13 region. PWS is animprinted condition with 70-75% of the cases due to a de novo deletionin the paternally inherited chromosome 15 11-q13 region, 20-30% frommaternal uniparental disomy 15 (UPD), and the remaining 2-5% from eithermicrodeletions or epimutations of the imprinting center (i.e.,imprinting defects) (Bittel and Butler, Expert Rev Mol Med 7(14): 1-20(2005); Cassidy and Driscoll, Eur J Hum Genet 17(1):3-13 (2009)).

The clinical manifestations of the condition begin in utero withdiminished fetal activity (Miller Am J Med Genet A 155A(5):1-10 (2011)).Low lean body mass and hypotonia are universal in PWS and presentthroughout life (Brambilla Am J Clin Nutr 65(5): 1369-1374 (1997),Lloret-lineras Int J Obes 37:1198-1203 (2013)). Mental retardationoccurs to varying degrees with the average IQ being 70 (PWSUSA). PWSpatients present with a range of behavioral complications includingautistic-spectrum-disorder-like behaviors, compulsive behaviors,self-injurious behaviors, and aggressive, threatening and destructivebehaviors. About 80% of PWS patients are growth hormone deficient(Goldstone, Trends Endocrinol Metab 15:12-120 (2004); Davies et al.,Front Neuroendocrinol 29:413-427 (2008); Cassidy and Driscoll, 2009,supra). Nearly all PWS patients are hypogonadal, requiring sex hormonesupplementation (Goldstone, 2004, supra; Davies et al., 2008, supra;Cassidy and Driscoll, 2009, supra). These patients have hypothalamicinsufficiency/dysfunction (Goldstone Am J Clin Nutr 75(3):468-475(2002)).

The accumulation of excess body fat may begin about age 2 and cancontinue into adulthood (Miller 2011, supra). The vast majority of bodyfat in PWS is subcutaneous (Brambilla 1997, supra; Sode-Carlson, Growthhormone and IGF research 20:179-184 (2010), Bedogni J Endocrinol InvestDOI 10.1007/s40618-015-0266-y (2015)). Obesity is not universal in PWS,unlike the universality of low lean body mass and hypotonia. Forexample, Sode-Carlson et al. (2010), supra, evaluated 46 adult PWSpatients, 25 women and 21 men. The average BMI in these adult PWSpatients was 27.2 kg/m². Thus, on average, these patients wereoverweight rather than obese, suggesting that more than half are not, infact, obese by the best metric. Similarly, Brambilla et al. Nutr MetabCardiovasc Dis 21(4):269-276 (2011) studied a population of 109 childrenwith PWS. They found that 54% were not classified as obese by the bestmetric. Thus, both in adults and in children with PWS, obesity is notonly not universal, but may, in fact, occur in less than half of thepopulation. Subcutaneous fat makes up a greater percentage of total fatin PWS than it does in obese controls at all ages (Sode-Carlson 2010,supra).

Hyperphagia with the associated problematic food related behaviorsbegins on average about age 8 (Miller 2011, supra). These patients sensethey are starving when they are not. Upon the onset of hyperphagia, PWSpatients will eat any food in the line of sight, get up at night to eat,dig through the trash for food, steal food, consume frozen food, petfood, spoiled food and even consume non-food items (Miller 2011, supra).They will become angry or throw tantrums if denied food. At this stageand thereafter throughout life, access to food is strictly limited, withcabinets and refrigerators being locked. To limit food related anxiety,meal times and meal composition are strictly regimented.

The mortality rate for PWS patients is three times that of the generalpopulation at all ages (Cassidy Genet Med 14(1): 10-26 (2012)), with theaverage age at death being about 29 years (PWSUSA mortality database,n=488). In contrast, being obese, but not morbidly obese has littleimpact on life expectancy (Anon (2011) National Research Council Panelon Understanding Divergent Trends in Longevity in High-Income Countries;Crimmons, E M, Preston, S H, Cohen, B, editors. National AcademiesPress).

Prader-Willi patients expend less energy and are more sedentary thaneither the general population, obese controls or patients with similarintellectual disabilities. Butler et al. Am J Med Gent A 143A(5):449-459(2007)) compared the energy expenditure and total work of a group of 48PWS patients with a group of 24 obese controls. Compared to thecontrols, PWS patients had significantly decreased total energyexpenditure (−20%), resting energy expenditure (−16%) and mechanicalwork (−35%). After adjusting for group differences in lean body mass,the difference remained significant for mechanical work.

In a study by van Mil et al., Int J Obes Relat Metab Disord24(4):429-434 (2000), the authors measured basal metabolic rate (BMR),average daily metabolic rate (ADMR), activity induced energy expenditure(AEE), and ADMR/BMR (PAL) in a group of PWS patients and matchedcontrols. ADMR, AEE and PAL were significantly lower (P<0.01) in the PWSgroup compared with the control group −28.2%, −58.2%, and −14.2%,respectively).

De Lind van Wijngaarden et al., J Clin Endocrinol Metab 95(4):1758-1766(2010) evaluated cardiovascular and metabolic risk factors in childrenwith PWS. They showed that 63% of infants and 73% of pre-pubertalchildren with PWS have at least one cardiovascular risk factor, definedas dyslipidemia or hypertension. Thus, the cardiometabolic risk in PWSis elevated even in younger children.

Preadipocyte: A progenitor cell to adipocytes.

Prediabetic: A condition that precedes diagnosis of type II diabetes.Type II diabetes is a form of diabetes mellitus which is characterizedby insulin insensitivity or resistance.

Prodrug: refers to a compound which, when metabolized, yields thedesired active compound. Typically, the prodrug is inactive, or lessactive than the active compound, but may provide advantageous handling,administration, or metabolic properties. For example, some prodrugs areesters of the active compound; during metabolysis, the ester group iscleaved to yield the active drug. Also, some prodrugs are activatedenzymatically to yield the active compound, or a compound which, uponfurther chemical reaction, yields the active compound.

Prolonged Administration (prolonged basis): Administration of apharmaceutically acceptable formulation of a drug for 7 or more days.Typically, prolonged administration is for at least two weeks,preferably at least one month, and even more preferably at least twomonths (i.e. at least 8 weeks).

Quick dissolving formulation: a pharmaceutical formulation which uponoral administration may release substantially all of the drug activefrom the formulation within 10 minutes.

Release formulation (sustained), (or “sustained release formulation”): Aformulation of pharmaceutical product that, upon administration toanimals, provides for release of the active pharmaceutical over anextended period of time than provided by formulations of the samepharmaceutical active that result in rapid uptake. Similar terms areextended-release, prolonged-release, and slow-release. In all cases, thepreparation, by definition, has a reduced rate of release of activesubstance.

Release formulation (delayed), (or “delayed release formulation”):Delayed-release products are modified-release, but are notextended-release. They involve the release of discrete amount(s) of drugsome time after drug administration, e.g. enteric-coated products, andexhibit a lag time during which little or no absorption occurs.

Release formulation (controlled), (or “controlled release formulation”):A formulation of pharmaceutical product that may include both delay ofrelease of pharmaceutical active upon administration and control ofrelease in the manner described for sustained release.

Salt: the neutral, basic or acid compound formed by the union of an acidor an acid radical and a base or basic radical.

Smith-Magenis syndrome (SMS; OMIM #182290, *607642): A complex,generally sporadic, genetic disorder caused by haploinsufficiency of theretinoic acid induced 1 (RAI1) gene. caused by either a 17p11.2 deletionencompassing the retinoic acid-induced 1 (RAI1) gene or a mutation ofRAI1. (see, for example, Burns et al., in Human Molecular Genetics,2010, Vol. 19, No. 20, pp. 4026-4042).

Smith-Magenis syndrome is characterized by a clinically recognizablephenotype that includes physical, developmental, neurological, andbehavioral features. Short stature (<5th percentile) was observed in−67% of young patients. Short stature resolves over time with mostindividuals reaching the 10-25th percentile by adulthood (see, forexample, Burns et al. supra). A majority of children with SMS also havesignificant early-onset obesity (see, for example, European Journal ofHuman Genetics (2008) 16, 412-421). Obesity in teens and adults iscommon, typically with broad chests and truncal obesity. RAI1haploinsufficiency represents a single-gene model of obesity withhyperphagia, abnormal fat distribution and altered hypothalamic geneexpression associated with satiety, food intake, behavior and obesity.

Hearing loss is variable and is often associated with chronic earinfections. Ophthalmologic features are present in >60% of SMS patientsand include myopia, iris anomalies, strabismus, microcornea, and,rarely, retinal detachment (often resulting from violent behaviors).

Prenatal history of SMS is notable for significantly decreased fetalmovement in 50% of pregnancies. Early infancy is complicated by feedingdifficulties leading to failure to thrive, marked oral sensory motordysfunction with poor suckling reflex, gastroesophageal reflux, andhypotonia.

Most SMS individuals have mild-to-moderate mental retardation. IQdecreases as the child ages, ultimately placing the individual in themild mental retardation range by adulthood. Delayed speech with orwithout hearing loss occurs in 96% of SMS patients. In addition, delayedfine/gross motor skills, problems with sensory integration, and pooradaptive function are seen. Other neurological features include pescavus or pes planus, an abnormal ‘festinating’ gait, balance problems,and a decreased sensitivity to pain, which is often observed inassociation with self-injury in this disorder.

Sleep disturbance has been reported in 75-100% of SMS cases. Infantstypically experience hypersomnolence during the first year of life.Sleep disturbances in older children include difficulties fallingasleep, diminished REM sleep, reduced 24-h and night sleep, fragmentedand shortened sleep cycles with frequent nocturnal and early-morningawakenings, and excessive daytime sleepiness.

Behavioral issues are one of the unique characteristic features of SMS.Maladaptive behaviors are a cause of major concern and include frequentoutbursts/temper tantrums, attention seeking, aggression, disobedience,distraction, and self-injurious behaviors. Self-injurious behaviorsinclude head banging, skin picking, wrist biting, onychotillomania andpolyembolokoilamania. The behavioral phenotype of SMS escalates withage, typically with the onset of puberty. Age, degree of developmentaldelay, severity of any associated systemic disorder, and degree of sleepdisturbance have a strong influence on maladaptive behaviors.Individuals also have a lack of respect for personal space during aconversation and are emotionally volatile.

SMS patients share many characteristics in common with PWS patients.These include: (1) diminished fetal activity; (2) hypotonia; (3) feedingdifficulties in early infancy; (4) short stature: (5) early onsetobesity which may include hyperphagia; (6) developmental delays; (7)mental retardation; (8) temper outbursts; (9) aggressive behavior; (10)self-injurious behavior; (11) hypersomnolence in infancy and similarsleep disturbances in older children and adults; (12) frequent earinfections; (13) scoliosis; and (14) strabismus. While the underlyinggenetic basis for these disorders is quite distinct, the presentationand natural history of the disease is very similar.

Solid oral dosage form: pharmaceutical formulations designed for oraladministration including capsules and tablets.

Subject: refers to animals, including mammals, such as human beings.

Sulfonylurea receptor: A component of the K_(ATP) channel responsiblefor interaction with sulfonylurea, other K_(ATP) channel antagonists,diazoxide and other K_(ATP) channel agonists.

Tablet: Pharmaceutical dosage form that is produced by forming a volumeof a matrix containing pharmaceutical active and excipients into a sizeand shape suitable for oral administration.

Thermogenesis: The physiological process of heat production in the body.

Threshold Concentration: The minimum circulating concentration of a drugrequired to exert a specific metabolic, physiological or compositionalchange in the body of a treated human or animal.

Treatment: means any manner in which the symptoms of a condition,disorder or disease or other indication, are ameliorated or otherwisebeneficially altered.

Triglyceride: Storage fats of animal and human adipose tissueprincipally consisting of glycerol esters of saturated fatty acids.

Type I diabetes: A chronic condition in which the pancreas makes littleor no insulin because the beta cells have been destroyed.

Uncoupling protein: A family of proteins that allow oxidation inmitochondria to proceed without the usual concomitant phosphorylation toproduce ATP.

Visceral fat: Human adipose tissues principally found below thesubcutaneous fat and muscle layer in the body.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 summarizes the change in hyperphagia score for all subjects whoparticipated in clinical study PC025.

FIG. 2 summarizes the percent change in lean body mass for all subjectswho participated in clinical study PC025.

FIG. 3 summarizes the percent change in body fat mass for all subjectswho participated in clinical study PC025.

FIG. 4 summarizes the percent change of the lean body mass/fat massratio for all subjects who participated in clinical study PC025.

FIG. 5 summarizes the clinical study treatment schedule for pediatricand adult patients who have PWS and are obese.

DETAILED DESCRIPTION OF THE INVENTION

Provided herein are pharmaceutical formulations of particular K_(ATP)channel openers that when administered to subjects achieve novelpharmacodynamic, pharmacokinetic, therapeutic, physiological, andmetabolic outcomes. Also provided are pharmaceutical formulations,methods of administration and dosing of particular K_(ATP) channelopeners, optionally in combination with growth hormone, that achievetherapeutic outcomes while reducing the incidence of adverse effects.

In particular, pharmaceutical formulations formulated for oraladministration exhibit advantageous properties including: facilitatingconsistency of absorption, pharmacokinetic and pharmacodynamic responsesacross treated patients, contributing to patient compliance andimproving the safety profile of the product, such as by reducing thefrequency of serious adverse effects. Method of treatment of metabolicand other diseases of humans and animals by administering theformulations are also provided.

Compounds of formulas II and III, formulas IV and V, and formulas VI andVII, such as for example, diazoxide (shown below) can be protontautomers. Proton tautomers are isomers that differ from each other onlyin the location of a hydrogen atom and a double bond. The hydrogen atomand double bond switch locations between a carbon atom and a heteroatom,such as for example N. Thus, when the nitrogen substituent is hydrogen,the two isomeric chemical structures may be used interchangeably.

The particular K_(ATP) channel openers that can be used in the inventionformulations include any of those within formulae I to VII. Exemplarysuch compounds include diazoxide, BPDZ62, BPDZ 73, NN414 and BPDZ 154(see, for example, Schou, et al., Bioorg. Med. Chem., 13, 141-155(2005)). Compound BPDZ 154 also is an effective K_(ATP) channelactivator in patients with hyperinsulinism and in patients withpancreatic insulinoma. The synthesis of BPDZ compound is provided inCosgrove, et al., J. Clin. Endocrinol. Metab., 87, 4860-4868 (2002).

Analogs of diazoxide include3-isopropylamino-7-methoxy-4H-1,2,4,-benzothiadiazine 1,1-dioxide, whichis a selective Kir6.2/SUR1 channel opener (see Dabrowski, et al.,Diabetes, 51, 1896-1906 (2002)). 2-alkyl substituted diazoxides areincluded (see, for example, Ouedraogo, et al., Biol. Chem., 383,1759-1768 (2002)); these channel openers show decreased activity in theinhibition of insulin release and increased activity in vascular smoothmuscle tissue. Furthermore, 2-alkyl substituted diazoxides generally donot function as traditional potassium channel activators, but insteadshow potential as Ca²⁺ blockers.

Other diazoxide analogs are described in Schou, et al., Bioorg. Med.Chem., 13, 141-155 (2005), and are shown below.

Diazoxide analogs having different alkyl substituents at the 3 positionof the molecule (identified as R³ shown below) are described inBertolino, et al., Receptors and Channels, 1, 267-278 (1993).

K_(ATP) channel activity of formulae I-VII and related compounds can bemeasured by membrane potential studies as described in Schou, et al.,Bioorg. Med. Chem., 13, 141-155 (2005) and Dabrowski, et al., Diabetes,51, 1896-1906 (2002).

Measurement of the inhibition of glucose-stimulated insulin release fromβTC6 cells is described in Schou, et al., Bioorg. Med. Chem., 13,141-155 (2005). The ability of particular K_(ATP) channel openers toinhibit release of insulin from incubated rat pancreatic islets can beperformed as described by Ouedraogo, et al., Biol. Chem., 383, 1759-1768(2002).

Activation of recombinant K_(ATP) channels by K_(ATP) channel openerscan be examined by monitoring macroscopic currents of inside-outmembrane patches from Xenopus oocytes coexpressing Kir6.2 and eitherSUR1, SUR2A or SUR2B. SUR expressing membranes can be prepared by knownmethods. See, for example, Dabrowski, et al., Diabetes, 51, 1896-1906(2002).

Binding experiments can be used to determine the ability of K_(ATP)channel openers to bind SUR1, SUR2A and SUR2B. See, for example,Schwanstecher, et al., EMBO J., 17, 5529-5535 (1998).

Preparation of SUR1 and SUR2A chimeras, as described by Babenko et al.,allows for comparison of pharmacologic profiles (i.e. sulfonylsensitivity and responsiveness to diazoxide or other potassium channelopeners) of the SUR1/Kir6.2 and SUR2A/Kir6.2 potassium channels. SeeBabenko, et al., J. Biol. Chem., 275(2), 717-720 (2000). The cloning ofa sulfonylurea receptor and an inwardly rectifying K⁺ channel isdescribed by Isomoto, et al., J. Biol. Chem., 271 (40), 24321-24324(1996); D'hahan, et al., PNAS, 96(21), 12162-12167 (1999).

Differences between the human SUR1 and human SUR2 genes are describedand shown in Aguilar-Bryan, et al., Physiological Review, 78(1), 227-245(1998).

“Halo” and “halogen” refer to all halogens, that is, chloro (Cl), fluoro(F), bromo (Br), or iodo (I).

“Hydroxyl” and “hydroxy” refer to the group —OH.

“Substituted oxy” refers to the group —OR^(f), where R^(f) is alkyl,substituted alkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, aralkyl, substituted aralkyl, cycloalkyl, substitutedcycloalkyl, heterocyclyl, or substituted heterocyclyl.

“Substituted thiol” refers to the group —SR, where R is alkyl,substituted alkyl, acyl, substituted acyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl, aralkyl, substituted aralkyl,cycloalkyl, substituted cycloalkyl, heterocyclyl, or substitutedheterocyclyl.

“Alkyl” refers to an alkane-derived radical containing from 1 to 10,preferably 1 to 6, carbon atoms. Alkyl includes straight chain alkyl,branched alkyl and cycloalkyl, such as methyl, ethyl, propyl, isopropyl,butyl, t-butyl, and the like. Straight chain or branched alkyl groupscontain from 1-10, preferably 1 to 6, more preferably 1-4, yet morepreferably 1-2, carbon atoms. The alkyl group is attached at anyavailable point to produce a stable compound.

A “substituted alkyl” is an alkyl group independently substituted with 1or more, e.g., 1, 2, or 3, groups or substituents such as halo, hydroxy,optionally substituted alkoxy, optionally substituted alkylthio,alkylsulfinyl, alkylsulfonyl, optionally substituted amino, optionallysubstituted amido, amidino, urea optionally substituted with alkyl,aminosulfonyl optionally N-mono- or N,N-di-substituted with alkyl,alkylsulfonylamino, carboxyl, heterocycle, substituted heterocycle,nitro, cyano, thiol, sulfonylamino or the like attached at any availablepoint to produce a stable compound. In particular, “fluro substituted”refers to substitution by 1 or more, e.g., 1, 2, or 3 fluorine atoms.“Optionally fluro substituted” means that substitution, if present, isfluoro.

“Lower alkyl” refers to an alkyl group having 1-6 carbon atoms.

A “substituted lower alkyl” is a lower alkyl which is substituted with 1or more, e.g., 1, 2, or 3, groups or substituents as defined above,attached at any available point to produce a stable compound.

“Cycloalkyl” refers to saturated or unsaturated, non-aromaticmonocyclic, bicyclic or tricyclic carbon ring systems of 3-8, morepreferably 3-6, ring members per ring, such as cyclopropyl, cyclopentyl,cyclohexyl, adamantyl, and the like. “Cycloalkylene” is a divalentcycloalkyl.

“Alkoxy” denotes the group —OR^(f), where R^(f) is lower alkyl.

“Substituted alkoxy” denotes the group —OR^(f), where R^(f) issubstituted lower alkyl.

“Alkylthio” or “thioalkoxy” refers to the group —S—R, where R is loweralkyl.

“Substituted alkylthio” or “substituted thioalkoxy” refers to the group—S—R, where R is substituted lower alkyl.

“Sulfinyl” denotes the group —S(O)—.

“Sulfonyl” denotes the group —S(O)₂—.

“Substituted sulfinyl” denotes the group —S(O)—R, where R is loweralkyl, substituted lower alkyl, cycloalkyl, substituted cycloalkyl,cycloalkylalkyl, substituted cycloalkylalkyl, heterocyclyl, substitutedheterocyclyl, heterocyclylalkyl, substituted hetereocyclylalkyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heteroaralkyl,substituted heteroaralkyl, aralkyl or substituted aralkyl.

“Substituted sulfonyl” denotes the group —S(O)₂—R, where R is loweralkyl, substituted lower alkyl, cycloalkyl, substituted cycloalkyl,cycloalkylalkyl, substituted cycloalkylalkyl, heterocyclyl, substitutedheterocyclyl, heterocyclylalkyl, substituted hetereocyclylalkyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heteroaralkyl,substituted heteroaralkyl, aralkyl or substituted aralkyl.

“Sulfonylamino” denotes the group —NRS(O)₂— where R is hydrogen or loweralkyl.

“Substituted sulfonylamino” denotes the group —NR^(a)S(O)₂—R^(b), whereR^(a) is hydrogen or lower alkyl and R^(b) is lower alkyl, substitutedlower alkyl, cycloalkyl, substituted cycloalkyl, heterocyclyl,substituted heterocyclyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, heteroaralkyl, substituted heteroaralkyl,aralkyl or substituted aralkyl.

“Amino” or “amine” denotes the group —NH₂. A “divalent amine” denotesthe group —NH—. A “substituted divalent amine” denotes the group —NR—wherein R is lower alkyl, substituted lower alkyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, acyl, substituted acyl,sulfonyl or substituted sulfonyl.

“Substituted amino” or “substituted amine” denotes the group—NR^(i)R^(j), wherein R^(i) and R^(j) are independently hydrogen, loweralkyl, substituted lower alkyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, acyl, substituted acyl, sulfonyl, substitutedsulfonyl, or cycloalkyl provided, however, that at least one of R^(i)and R^(j) is not hydrogen. R^(i)R^(j) in combination with the nitrogenmay form an optionally substituted heterocyclic or heteroaryl ring.

“Alkylsulfinyl” denotes the group —S(O)R^(p), wherein R^(p) isoptionally substituted alkyl.

“Alkylsulfonyl” denotes the group —S(O)₂R^(p), wherein R^(p) isoptionally substituted alkyl.

“Alkylsulfonylamino” denotes the group —NR^(q)S(O)₂R^(p), wherein R^(p)is optionally substituted alkyl, and R^(q) is hydrogen or lower alkyl.

Pharmaceutical formulations containing K_(ATP) channel openers includethe free base of the drug or a salt of the drug. Such salts may have oneor more of the following characteristics: (1) stability in solutionduring synthesis and formulation, (2) stability in a solid state, (3)compatibility with excipients used in the manufacture of tabletformulations, (4) quantitatively yield the K_(ATP) channel opener uponexposure to simulated or actual gastric and duodenal conditions, (5)release K_(ATP) channel opener from sufficiently small particles thatare readily dissolved and absorbed, (6) provide, when incorporated intoa pharmaceutical formulation, for absorption of greater than 80% of theadministered dose, (7) present no elevated toxicological risk ascompared to the free base of the K_(ATP) channel opener, (8) can beformulated into acceptable pharmaceutical formulations to treat obesityand other diseases of humans, (9) are acceptable to the FDA as the basisof a drug product, (10) can be recrystallized to improve purity, (11)can be used to form co-crystals of two or more salts of the K_(ATP)channel opener, (12) have limited hygroscopicity to improve stability,or (13) synthetic and crystallization conditions under which the salt isformed can be varied resulting in different crystal structures(polymorphs) can be controlled in the synthesis of the salt.

K_(ATP) channel openers can be formulated as pharmaceutically acceptablesalts. Pharmaceutically acceptable salts are non-toxic salts in theamounts and concentrations at which they are administered. Thepreparation of such salts can facilitate the pharmacological use byaltering the physical characteristics of a compound without preventingit from exerting its physiological effect. Useful alterations inphysical properties include lowering the melting point to facilitatetransmucosal administration and increasing the solubility to facilitateadministering lower effective doses of the drug.

Pharmaceutically acceptable salts include acid addition salts such asthose containing sulfate, chloride, hydrochloride, fumarate, maleate,phosphate, sulfamate, acetate, citrate, lactate, tartrate,methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate,cyclohexylsulfamate and quinate. Pharmaceutically acceptable salts canbe obtained from acids such as hydrochloric acid, maleic acid, sulfuricacid, phosphoric acid, sulfamic acid, acetic acid, citric acid, lacticacid, tartaric acid, malonic acid, methanesulfonic acid, ethanesulfonicacid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamicacid, fumaric acid, and quinic acid.

Pharmaceutically acceptable salts also include basic addition salts suchas those containing benzathine, chloroprocaine, choline, diethanolamine,ethylenediamine, meglumine, procaine, aluminum, calcium, lithium,magnesium, potassium, sodium, ammonium, alkylamine, and zinc, whenacidic functional groups, such as carboxylic acid or phenol are present.For example, see Remington's Pharmaceutical Sciences, 19^(th) ed., MackPublishing Co., Easton, Pa., Vol. 2, p. 1457, 1995. Such salts can beprepared using the appropriate corresponding bases.

Pharmaceutically acceptable salts can be prepared, for example, bydissolving the free-base form of a compound in a suitable solvent, suchas an aqueous or aqueous-alcohol in solution containing the appropriateacid and then isolated by evaporating the solution. In another example,a salt is prepared by reacting the free base and acid in an organicsolvent.

The pharmaceutically acceptable salt of the different compounds may bepresent as a complex. Examples of complexes include 8-chlorotheophyllinecomplex (analogous to, e.g., dimenhydrinate:diphenhydramine8-chlorotheophylline (1:1) complex; Dramamine) and various cyclodextrininclusion complexes.

Salts of K_(ATP) channel openers, and particular salts of diazoxide, mayinclude, but are not limited to acetate, acetonide, acetyl, adipate,aspartate, besylate, biacetate, bitartrate, bromide, butoxide, butyrate,calcium, camsylate, caproate, carbonate, citrate, cyprionate, decaroate,diacetate, dimegulumine, dinitrate, dipotassium, dipropionate, disodium,disulfide, edisylate, enanthate, estolate, etabonate, ethylsuccinate,fumarate, furoate, gluceptate, gluconate, hexacetonide, hippurate,hyclate, hydrobromide, hydrochloride, isethionate, lactobionate, malate,maleate, meglumine, methylbromide, methylsulfate, metrizoate, nafate,napsylate, nitrate, oleate, palmitate, pamoate, phenpropionate,phosphate, pivalate, polistirex, polygalacturonate, probutate,propionate, saccharate, sodium glycinate, sodium phosphate, podiumsuccinate, state, succinate, sulfate, sulfonate, sulfosalicylate,tartrate, tebutate, terephalate, terephthalate, tosylate, triflutate,trihydrate, trisilicate, tromethamine, valerate, xinafolate, or thelike.

Formulations provided herein exhibit some or all the followingcharacteristics: (1) they are stable at ambient temperatures for aminimum of one year; (2) they provide for ease of oral administration;(3) they facilitate patient compliance with dosing; (4) uponadministration, they consistently facilitate high levels of absorptionof the pharmaceutical active; (5) upon once or twice daily oraladministration they allow release of the K_(ATP) channel opener over asustained time frame such that the circulating concentration of theK_(ATP) channel opener or its metabolically active metabolites does notfall below a therapeutically effective concentration; (6) they achievethese results independent of the pH of the gastrointestinal tract oftreated individuals, and (7) they delay release until gastric transit iscomplete or nearly complete.

Formulations designed for oral administration can be provided, forexample, as capsules or tablets. Capsule or tablet formulations includea number of distinguishing components. One is a component to improveabsorption of the K_(ATP) channel opener. Another sustains release ofthe drug over more than 2 hours. A third delays substantial release ofthe drug until gastric transit is completed.

The formulations disclosed herein exhibit improved solubility andabsorption of the K_(ATP) channel opener compared to previousformulations of these drugs. These advantageous properties are achievedby any one or more of the following approaches: (1) reducing particlesize of the formulation by comminution, spray drying, or othermicronising techniques, (2) using a pharmaceutical salt of the K_(ATP)channel opener, (3) using an ion exchange resin in the formulation, (4)using inclusion complexes, for example using a cyclodextrin, (5)compaction of the K_(ATP) channel opener with a solubilizing agentincluding low viscosity hypromellose, low viscosity metylcellulose orsimilarly functioning excipient and combinations thereof, (6)associating the K_(ATP) channel opener with a salt prior to formulation,(7) using a solid dispersion of the K_(ATP) channel opener, (8) using aself emulsifying system, (9) adding one or more surfactants to theformulation, (10) using nanoparticles in the formulation, or (11)combinations of these approaches. Preferably, when the K_(ATP) channelopener is a salt of diazoxide, the salt is not a sodium salt.

Release of K_(ATP) channel opener over a sustained period of time (2-24hours) is achieved by the use of one or more approaches including, butnot limited to: (1) the use of pH sensitive polymeric coatings, (2) theuse of a hydrogel, (3) the use of a film coating that controls the rateof diffusion of the drug from a coated matrix, (4) the use of anerodable matrix that controls rate of drug release, (5) the use ofpolymer coated pellets, granules, or microparticles which can be furtherencapsulated or compressed into a tablet, (6) the use of an osmotic pumpsystem, or (7) the use of a compression coated tablet, or (8)combinations of these approaches.

Delay of release of K_(ATP) channel openers from the formulation untilgastric transit is complete is achieved in the formulations providedherein by any of several mechanisms. A pH sensitive polymer orco-polymer is used which when applied around the drug matrix functionsas an effective barrier to release of active at pH 3.0 or lower and isunstable at pH 5.5 and above. This provides for control of release ofthe active compound in the stomach but rapidly allows release once thedosage form has passed into the small intestine. An alternative to a pHsensitive polymer or co-polymer is a polymer or co-polymer that isnon-aqueous-soluble. The extent of resistance to release in the gastricenvironment can be controlled by coating with a blend of thenon-aqueous-soluble and a aqueous soluble polymer. In this approachneither of the blended polymers or co-polymers are pH sensitive. Oneexample of a pH sensitive co-polymer is the Eudragit methacrylicco-polymers, including Eudragit L100, S100 or L100-55 solids, L30 D-55or FS 30D dispersions, or the L12.5 or S12.5 organic solutions.

Polymers that delay release can be applied to a tablet either by spraycoating (as a thin film) or by compression coating. If a capsule isused, then the polymer(s) may be applied over the surface of the capsuleor applied to microparticles of the drug, which may then be encapsulatedsuch as in a capsule or gel. If the capsule is coated, then it willresist disintegration until after gastric transit. If microparticles arecoated, then the capsule may disintegrate in the stomach but little tono drug will be released until after the free microparticles completegastric transit. Finally, an osmotic pump system that uses e.g., aswellable hydrogel can be used to delay drug release in the stomach. Theswellable hydrogel takes up moisture after administration. Swelling ofthe gel results in displacement of the drug from the system forabsorption. The timing and rate of release of the drug depend on the gelused, and the rate at which moisture reaches the gel, which can becontrolled by the size of the opening in the system through which fluidenters. See Drug Delivery Technologies online article Dong et al.“L-OROS® SOFTCAP™ for Controlled Release of Non-Aqueous LiquidFormulations.”

Accordingly, delay of release of K_(ATP) channel openers from theinvention formulations until after gastric transit is complete isachieved in the formulations provided herein by any of severalmechanisms, including, but not limited to: (a) a pH sensitive polymer orco-polymer applied as a compression coating on a tablet; (b) a pHsensitive polymer or co-polymer applied as a thin film on a tablet; (c)a pH sensitive polymer or co-polymer applied as a thin film to anencapsulation system; (d) a pH sensitive polymer or co-polymer appliedto encapsulated microparticles, (e) a non-aqueous-soluble polymer orco-polymer applied as a compression coating on a tablet; (f) anon-aqueous-soluble polymer or co-polymer applied as a thin film on atablet; (g) a non-aqueous soluble polymer applied as a thin film to anencapsulation system; (h) a non-aqueous soluble polymer applied tomicroparticles; (i) incorporation of the formulation in an osmotic pumpsystem, or (j) use of systems controlled by ion exchange resins, or (k)combinations of these approaches, wherein the pH sensitive polymer orco-polymer is resistant to degradation under acid conditions.

Formulations are provided that are designed for administration oncedaily (per 24 hours). These can contain between 25 and 500 mg of K_(ATP)channel openers. Formulations intended for administration twice daily(per 24 hours) are also provided. These can contain between 25 and 250mg of K_(ATP) channel openers.

The formulations provided herein exhibit improved safety of theadministered drug product. This improvement in safety occurs by at leasttwo mechanisms. First, delay of release of active drug until gastrictransit is complete can reduce the incidence of a range ofgastrointestinal adverse side effects including nausea, vomiting,dyspepsia, abdominal pain, diarrhea and ileus. Second, by sustainingrelease of the active drug over 2 or more hours to as long as 24 hours,peak drug levels are reduced relative to the peak drug levels observedfor the same administered dose using any oral formulation that does nothave sustained or controlled release. This reduction in peak drug levelscan contribute to reductions in adverse effects that are partially orcompletely determined by peak drug levels. These adverse effectsinclude: fluid retention with the associated reduced rates of excretionof sodium, chloride and uric acid, edema, hyperglycemia and theassociated potential for progression to ketoacidosis, cataracts andnon-ketotic hyperosmolar coma, headaches, tachycardia and palpitations.

Also provided herein are controlled release formulations of K_(ATP)channel openers, which have one feature from each of A-D as shown inTable 1.

TABLE 1 Controlled Release Formulation Characteristics and Properties A.Unit Form: Tablet or Capsule B. Dosage/unit: 10-100 mg 100-200 mg200-300 mg 300-500 mg 500-2000 mg C. Dosing Once daily (24 hours) Twicedaily (24 hours) D. Release time: 2-4 hrs 4-8 hrs 8-24 hours

For example, a controlled release composition can be a tablet containing25-100 mg of a K_(ATP) channel opener, such tablet administered oncedaily to achieve a controlled release time of 2-4 hours. All of theseformulations can further include the feature of substantially delayingpharmaceutical active release until after gastric transit is complete.

In addition, any of the above formulations from Table 1 can include atleast one feature that improves the solubility or absorption of theK_(ATP) channel opener.

The controlled release formulations provided herein comprise the activecompound (e.g., K_(ATP) channel opener, optionally in combination withgrowth hormone) and a matrix which comprises a gelling agent that swellsupon contact with aqueous fluid. The active compound(s) entrapped withinthe gel is(are) slowly released into the body upon dissolution of thegel. The active compound(s) can be evenly dispersed within the matrix orcan be present as pockets of drug in the matrix. For example, the drugcan be formulated into small granules which are dispersed within thematrix. In addition, the granules of drug also can include a matrix,thus, providing a primary and a secondary matrix as described in U.S.Pat. No. 4,880,830 to Rhodes.

The gelling agent preferably is a polymeric material, which can include,for example, any pharmaceutically acceptable water soluble or waterinsoluble slow releasing polymer such as xantham gum, gelatin, celluloseethers, gum arabic, locust bean gum, guar gum, carboxyvinyl polymer,agar, acacia gum, tragacanth, veegum, sodium alginate or alginic acid,polyvinylpyrrolidone, polyvinyl alcohol, or film forming polymers suchas methyl cellulose (MC), carboxymethyl cellulose (CMC), hydroxypropylmethylcellulose, hyroxypropyl methyl cellulose (HPMC), hydroxypropylcellulose (HPC), hydroxyethyl cellulose (HEC), ethylcellulose (EC),acrylic resins or mixtures of the above (see e.g., U.S. Pat. No.5,415,871).

The gelling agent of the matrix also can be a heterodisperse gumcomprising a heteropolysaccharide component and a homopolysaccharidecomponent which produces a fast-forming and rigid gel as described inU.S. Pat. No. 5,399,359. The matrix also can include a crosslinkingagent such as monovalent or multivalent metal cations to further addrigidity and decrease dissolution of the matrix, thus further slowingrelease of drug. The amount of crosslinking agent to add can bedetermined using methods routine to the ordinary skilled artisan.

The matrix of the controlled release composition also can include one ormore pharmaceutically acceptable excipients recognized by those skilledin the art, i.e. formulation excipients. Such excipients include, forexample, binders: polyvinylpyrrolidone, gelatin, starch paste,microcrystalline cellulose; diluents (or fillers): starch, sucrose,dextrose, lactose, fructose, xylitol, sorbitol, sodium chloride,dextrins, calcium phosphate, calcium sulphate; and lubricants: stearicacid, magnesium stearate, calcium stearate, Precirol™ and flow aids forexample talc or colloidal silicon dioxide.

The matrix of the controlled release composition can further include ahydrophobic material which slows the hydration of the gelling agentwithout disrupting the hydrophilic nature of the matrix, as described inU.S. Pat. No. 5,399,359. The hydrophobic polymer can include, forexample, alkylcellulose such as ethylcellulose, other hydrophobiccellulosic materials, polymers or co-polymers derived from acrylic ormethacrylic acid esters, co-polymers of acrylic and methacrylic acidesters, zein, waxes, shellac, hydrogenated vegetable oils, waxes andwaxy substances such as carnauba wax, spermaceti wax, candellila wax,cocoa butter, cetosteryl alcohol, beeswax, ceresin, paraffin, myristylalcohol, stearyl alcohol, cetylalcohol and stearic acid. and any otherpharmaceutically acceptable hydrophobic material known to those skilledin the art.

The amount of hydrophobic material incorporated into the controlledrelease composition is that which is effective to slow the hydration ofthe gelling agent without disrupting the hydrophilic matrix formed uponexposure to an environmental fluid. In certain preferred embodiments,the hydrophobic material is included in the matrix in an amount fromabout 1 to about 20 percent by weight and replaces a correspondingamount of the formulation excipient. A solvent for the hydrophobicmaterial may be an aqueous or organic solvent, or mixtures thereof.

Examples of commercially available alkylcelluloses are Aquacoat®(aqueous dispersion of ethylcellulose available from FMC) and Surelease®(aqueous dispersion of ethylcellulose available from Colorcon). Examplesof commercially available acrylic polymers suitable for use as thehydrophobic material include Eudragit® RS and RL (co-polymers of acrylicand methacrylic acid esters having a low content (e.g., 1:20 or 1:40) ofquaternary ammonium compounds).

The controlled release composition also can be coated to retard accessof liquids to the active compound and/or retard release of the activecompound through the film-coating. The film-coating can providecharacteristics of gastroresistance and enterosolubility by resistingrapid dissolution of the composition in the digestive tract. Thefilm-coating generally represents about 5-15% by weight of thecontrolled release composition. Preferably, the core by weightrepresents about 90% of the composition with the remaining 10% providedby the coating. Such coating can be a film-coating as is well known inthe art and include gels, waxes, fats, emulsifiers, combination of fatsand emulsifiers, polymers, starch, and the like.

Polymers and co-polymers are useful as thin film coatings. Solutioncoatings and dispersion coatings can be used to coat the activecompound, either alone or combined with a matrix. The coating ispreferably applied to the drug or drug and matrix combination as a solidcore of material as is well known in the art.

A solution for coating can include polymers in both organic solvent andaqueous solvent systems, and typically further including one or morecompounds that act as a plasticizer. Polymers useful for coatingcompositions include, for example, methylcellulose (Methocel® A; DowChemical Co.), hydroxypropylmethylcellulose with a molecular weightbetween 1,000 and 4,000,000 (Methocel® E; Dow Chemical Co. orPharmacoat®; Shin Etsu), hydroxypropyl cellulose with a molecular weightbetween 2,000 and 2,000,000, ethyl cellulose, cellulose acetate,cellulose triacetate, cellulose acetate butyrate, cellulose acetatephthalate, cellulose acetate trimellitate (Eastman Kodak),carboxymethylethyl cellulose (Duodcel®), hydroxypropyl methylcellulosephthalate, ethylcellulose, methylcellulose and, in general, cellulosicderivatives, olymethacrylic acid-methacrylic acid co-polymer (Type A 1:1Eudragit L100; Type B 1:2 Eudragit S100; and Type C 1:1 EudragitL100-55, aqueous dispersion 30% solids, Eudragit L30D), poly(meth)acrylester: poly(ethyl acrylate, methyl methacrylate 2:1), Eudragit NE30Daqueous dispersion 30% solids, polyaminomethacrylate Eudragit E100,poly(trimethylammonioethyl methacrylate chloride)ammoniomethacrylateco-polymer, Eudragit RL30D and Eudragit RS30D, carboxyvinyl polymers,polyvinylalcohols, glucans scleroglucans, mannans, and xanthans.

Aqueous polymeric dispersions include Eudragit L30D and RS/RL30D, andNE30D, Aquacoat brand ethyl cellulose, Surelease brand ethyl cellulose,EC brand N-10F ethyl cellulose, Aquateric brand cellulose acetatephthalate, Coateric brand Poly(vinyl acetate phthalate), and Aqacoatbrand hydroxypropyl methylcellulose acetate succinate. Most of thesedispersions are latex, pseudolatex powder or micronized powder mediums.

A plasticizing agent may be included in the coating to improve theelasticity and the stability of the polymer film and to prevent changesin the polymer permeability over prolonged storage. Such changes mayaffect the drug release rate. Suitable conventional plasticizing agentsinclude, for example, diethyl phthalate, glycerol triacetate, acetylatedmonoglycerides, acetyltributylcitrate, acetyltriethyl citrate, castoroil, citric acid esters, dibutyl phthalate, dibutyl sebacate,diethyloxalate, diethyl malate, diethylfumarate, diethylphthalate,diethylsuccinate, diethylmalonate, diethyltartarate, dimethylphthalate,glycerin, glycerol, glyceryl triacetate, glyceryltributyrate, mineraloil and lanolin alcohols, petrolatum and lanolin alcohols, phthalic acidesters, polyethylene glycols, propylene glycol, rape oil, sesame oil,triacetin, tributyl citrate, triethyl citrate, and triethyl acetylcitrate, or a mixture of any two or more of the foregoing. Plasticizerswhich can be used for aqueous coatings include, for example, propyleneglycol, polyethylene glycol (PEG 400), triacetin, polysorbate 80,triethyl citrate, and diethyl d-tartrate.

A coating solution comprising a mixture of hydroxypropylmethylcelluloseand aqueous ethylcellulose (e.g. Aquacoat brand) as the polymer anddibutyl sebacate as plasticizer can be used for coating microparticles.(Aquacoat is an aqueous polymeric dispersion of ethylcellulose andcontains sodium lauryl sulfate and cetyl alcohol). Preferably, theplasticizer represents about 1-2% of the composition.

In addition to the polymers, the coating layer can include an excipientto assist in formulation of the coating solution. Such excipients mayinclude a lubricant or a wetting agent. Suitable lubricants asexcipients for the film coating include, for example, talc, calciumstearate, colloidal silicon dioxide, glycerin, magnesium stearate,mineral oil, polyethylene glycol, and zinc stearate, aluminum stearateor a mixture of any two or more of the foregoing. Suitable wettingagents include, for example, sodium lauryl sulfate, acacia, benzalkoniumchloride, cetomacrogol emulsifying wax, cetostearyl alcohol, cetylalcohol, cholesterol, diethanolamine, docusate sodium, sodium stearate,emulsifying wax, glyceryl monostearate, hydroxypropyl cellulose, lanolinalcohols, lecithin, mineral oil, onoethanolamine, poloxamer,polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives,polyoxyethylene sorbitan fatty acid esters, polyoxyethylene stearates,propylene glycol alginate, sorbitan esters, stearyl alcohol andtriethanolamine, or a mixture of any two or more of the foregoing.

The specified tablet or capsule formulations of Table 1 may includeco-formulation with an obesity treating drug (in addition to the K_(ATP)channel opener). Obesity treating drugs that may be used include, butare not limited to, sibutramine hydrochloride (5-30 mg/unit), orlistat(50-360 mg/unit), phentermine hydrochloride or resin complex (15 to 40mg/unit), zonisamide (100 to 600 mg/unit) topiramate (64 to 400mg/unit), naltrexone hydrochloride (50 to 600 mg/unit), rimonabant (5 to20 mg/unit), ADP356 (5 to 25 mg/unit), ATL962 (20 to 400 mg/unit), orAOD9604 (1 to 10 mg/unit). These formulations are preferably used oncedaily. For a twice daily dosing, the amount of K_(ATP) channel opener isone half the amount included in the once daily formulation and thecoformulated obesity treating drug is half of the amount specified.Alternative obesity treating drugs may include: selective serotonin 2 creceptor agonists, dopamine antagonists, cannabinoid-1 receptorantagonists, leptin analogues, leptin transport and/or leptin receptorpromoters, neuropeptide Y and agouti-related peptide antagonists,proopiomelanocortin and cocaine and amphetamine regulated transcriptpromoters, melanocyte-stimulating hormone analogues, melanocortin-4receptor agonists, and agents that affect insulin metabolism/activity,which include protein-tyrosine phosphatase-1B inhibitors, peroxisomeproliferator activated receptor-receptor antagonists, short-actingbromocriptine (ergoset), somatostatin agonists (octreotide), andadiponectin, gastrointestinal-neural pathway agents, including thosethat increase cholecystokinin activity, increase glucagon-like peptide-1activity (extendin 4, liraglutide, dipeptidyl peptidase IV inhibitors),and increase protein YY3-36 activity and those that decrease ghrelinactivity, as well as amylin analogues, agents that may increase restingmetabolic rate (“selective” β-3 stimulators/agonist, uncoupling proteinhomologues, and thyroid receptor agonists), melanin concentratinghormone antagonists, phytostanol analogues, amylase inhibitors, growthhormone fragments, synthetic analogues of dehydroepiandrosteronesulfate, antagonists of adipocyte 11Bhydroxysteroid dehydrogenase type 1activity, corticotropin releasing hormone agonists, inhibitors of fattyacid synthesis, carboxypeptidase inhibitors, indanones/indanols,aminosterols, and other gastrointestinal lipase inhibitors.

The specified tablet or capsule formulations of Table 1 may includeco-formulation with a diabetes treating drug (in addition to the K_(ATP)channel opener). Diabetes treating drugs that may be used include, butare not limited to acarbose (50 to 300 mg/unit), miglitol (25 to 300mg/unit), metformin hydrochloride (300 to 2000 mg/unit), repaglinide(1-16 mg/unit), nateglinide (200 to 400 mg/unit), rosiglitizone (5 to 50mg/unit), metaglidasen (100 to 400 mg/unit) or any drug that improvesinsulin sensitivity, or improves glucose utilization and uptake. Theseformulations are preferably used once daily. For a twice daily dosing,the amount of the K_(ATP) channel opener is half the amount included inthe once daily formulation and the co-formulated diabetes treating drugis half of the amount specified.

The specified tablet or capsule formulations of Table 1 may includeco-formulation with a cholesterol lowering drug. Cholesterol loweringdrugs that may be used include, but are not limited to pravastatin orsimvastatin or atorvastatin or fluvastatin or rosuvastatin or lovastatin(all at 10 to 80 mg/unit). These formulations are preferably used oncedaily. For a twice daily dosing, the amount of K_(ATP) channel opener ispreferably 25 to 200 mg/unit and the coformulated cholesterol loweringdrug is half of the amount specified.

The specified tablet or capsule formulations of Table 1 may includeco-formulation with a depression treating drug. Depression treatingdrugs that may be used include, but are not limited to citalopramhydrobromide (10 to 80 mg/unit), escitalopram hydrobromide (5 to 40mg/unit), fluvoxamine maleate (25 to 300 mg/unit), paroxetinehydrochloride (12.5 to 75 mg/unit), fluoxetine hydrochloride (30 to 100mg/unit), setraline hydrochloride (25 to 200 mg/unit), amitriptylinehydrochloride (10 to 200 mg/unit), desipramine hydrochloride (10 to 300mg/unit), nortriptyline hydrochloride (10 to 150 mg/unit), duloxetinehydrochloride (20 to 210 mg/unit), venlafaxine hydrochloride (37.5 to150 mg/unit), phenelzine sulfate (10 to 30 mg/unit), bupropionhydrochloride (200 to 400 mg/unit), or mirtazapine (7.5 to 90 mg/unit).These formulations are preferably used once daily. For a twice dailydosing, the amount of K_(ATP) channel opener is preferably half theamount included in the once daily formulation and the coformulateddepression treating drug is half of the amount specified.

The specified tablet or capsule formulations of Table 1 may includeco-formulation with a hypertension treating drug. Hypertension treatingdrugs that may be used include, but are not limited to enalapril maleate(2.5 to 40 mg/unit), captopril (2.5 to 150 mg/unit), lisinopril (10 to40 mg/unit), benzaepril hydrochloride (10 to 80 mg/unit), quinaprilhydrochloride (10 to 80 mg/unit), peridopril erbumine (4 to 8 mg/unit),ramipril (1.25 to 20 mg/unit), trandolapril (1 to 8 mg/unit), fosinoprilsodium (10 to 80 mg/unit), moexipril hydrochloride (5 to 20 mg/unit),losartan potassium (25 to 200 mg/unit), irbesartan (75 to 600 mg/unit),valsartan (40 to 600 mg/unit), candesartan cilexetil (4 to 64 mg/unit),olmesartan medoxamil (5 to 80 mg/unit), telmisartan (20 to 160 mg/unit),eprosartan mesylate (75 to 600 mg/unit), atenolol (25 to 200 mg/unit),propranolol hydrochloride (10 to 180 mg/unit), metoprolol tartrate,succinate or fumarate (all at 25 to 400 mg/unit), nadolol (20 to 160mg/unit), betaxolol hydrochloride (10 to 40 mg/unit), acebutololhydrochloride (200 to 800 mg/unit), pindolol (5 to 20 mg/unit),bisoprolol fumarate (5 to 20 mg/unit), nifedipine (15 to 100 mg/unit),felodipine (2.5 to 20 mg/unit), amlodipine besylate (2.5 to 20 mg/unit),nicardipine (10 to 40 mg/unit), nisoldipine (10 to 80 mg/unit),terazosin hydrochloride (1 to 20 mg/unit), doxasoxin mesylate (4 to 16mg/unit), prazosin hydrochloride (2.5 to 10 mg/unit), or alfuzosinhydrochloride (10 to 20 mg/unit). These formulations are preferably usedonce daily. For a twice daily dosing, the amount of K_(ATP) channelopener is preferably half the amount included in the once dailyformulation and the coformulated hypertension treating drug is half ofthe amount specified.

The specified tablet or capsule formulations of Table 1 may includeco-formulation with a diuretic to treat edema. Diuretics that may beused include, but are not limited to amiloride hydrochloride (1 to 10mg/unit), spironolactone (10 to 100 mg/unit), triamterene (25 to 200mg/unit), bumetanide (0.5 to 4 mg/unit), furosemide (10 to 160 mg/unit),ethacrynic acid or ethacrynate sodium (all at 10 to 50 mg/unit),tosemide (5 to 100 mg/unit), chlorthalidone (10 to 200 mg/unit),indapamide (1 to 5 mg/unit), hydrochlorothiazide (10 to 100 mg/unit),chlorothiazide (50 to 500 mg/unit), bendroflumethiazide (5 to 25mg/unit), hydroflumethiazide (10 to 50 mg/unit), mythyclothiazide (1 to5 mg/unit), or polythiazide (1 to 10 mg/unit). These formulations arepreferably used once daily. For a twice daily dosing, the amount ofK_(ATP) channel opener is preferably half the amount included in theonce daily formulation and the coformulated diuretic is half of theamount specified.

The specified tablet or capsule formulations of Table 1 may includeco-formulation with a drug to treat inflammation or pain. Drugs fortreating inflammation or pain that may be used include, but are notlimited to aspirin (100 to 1000 mg/unit), tramadol hydrochloride (25 to150 mg/unit), gabapentin (100 to 800 mg/unit), acetominophen (100 to1000 mg/unit), carbamazepine (100 to 400 mg/unit), ibuprofen (100 to1600 mg/unit), ketoprofen (12 to 200 mg/unit), fenprofen sodium (100 to600 mg/unit), flurbiprofen sodium or flurbiprofen (both at 50 to 200mg/unit), or combinations of any of these with a steroid or aspirin.These formulations are preferably used once daily. For a twice dailydosing, the amount of K_(ATP) channel opener is preferably half theamount included in the once daily formulation and the coformulateddiuretic is half of the amount specified.

The specified tablet or capsule formulations of Table 1 may includeco-formulation with a drug to treat obesity associated comorbiditiesinclude those specified above for treating diabetes, cholesterol,depression, hypertension and edema, or drugs to treat atherosclerosis,osteoarthritis, disc herniation, degeneration of knees and hips, breast,endometrial, cervical, colon, leukemia and prostate cancers,hyperlipidemia, asthma/reactive airway disease, gallstones, GERD,obstructive sleep apnea, obesity hypoventilation syndrome, recurrentventral hernias, menstrual irregularity and infertility.

The specified tablet or capsule formulations of Table 1 may includeco-formulation with an anti-psychotic drug the combination used to treatthe psychotic condition and to treat or prevent weight gain,dyslipidemia or impaired glucose tolerance in the treated individual.Drugs for treating various psychotic conditions that may be usedinclude, but are not limited to, lithium or a salt thereof (250 to 2500mg/unit), carbamazepine or a salt thereof (50 to 1200 mg/unit),valproate, valproic acid, or divalproex (125 to 2500 mg/unit),lamotrigine (12.5 to 200 mg/unit), olanzapine (5 to 20 mg/unit),clozapine (12.5 to 450 mg/unit), or risperidone (0.25 to 4 mg/unit).These coformulations are preferably intended for once per dayadministration. For a twice daily dosing, the amount of K_(ATP) channelopener is preferably half the amount included in the once dailyformulation and the coformulated anti-psychotic is half of the amountspecified.

The specified tablet or capsule formulations of Table 1 may includeco-formulation with a drug to treat or prevent ischemic or reperfusioninjury. Drugs for treating or preventing ischemic or reperfusion injurythat may be used include, but are not limited to: low molecular weightheparins (dalteparin, enoxaparin, nadroparin, tinzaparin or danaparoid),ancrd, pentoxifylline, nimodipine, flunarizine, ebselen, tirilazad,clomethiazole, an AMPA agonist (GYKI 52466, NBQX, YM90K, zonampanel,orMPQX), SYM 2081, selfotel, Cerestat, CP-101,606, dextrophan,dextromethorphan, MK-801, NPS 1502, remacemide, ACEA 1021, GV150526,eliprodil ifenprodil, lubeluzole, naloxone, nalfemene citicoline,acetyl-1-carnitine, nifedipine, resveratrol, a nitrone derivative,clopidogrel, dabigatram, prasugrel, troxoprodil, AGY-94806, or KAI-9803.

Provided are formulations administered once or twice daily to an obeseor overweight subject continuously to result in a circulatingconcentration of K_(ATP) channel opener sufficient to induce weightloss. Weight loss occurs by the preferential loss of body fat.Additional weight loss can occur when the formulation is administered incombination with a reduced calorie diet.

Provided are formulations of K_(ATP) channel openers administered as asingle dose to an obese, overweight or obesity-prone subject that resultin the inhibition of fasting or glucose stimulated insulin secretion forabout 24 hours or for about 18 hours.

Provided are formulations of K_(ATP) channel openers administered as asingle dose to an obese, overweight or obesity-prone subject that resultin the elevation of energy expenditure for about 24 hours or for about18 hours.

Provided are formulations of K_(ATP) channel openers administered as asingle dose to an obese, overweight or obesity-prone subject that resultin the elevation of beta oxidation of fat for about 24 hours or forabout 18 hours.

Provided are formulations of K_(ATP) channel openers administered as asingle dose to an obese, overweight or obesity-prone hyperphagic subjectthat result in the inhibition of hyperphagia for about 24 hours or forabout 18 hours.

Provided are formulations administered once or twice daily (per 24hours) to a subject continuously result in a circulating concentrationof K_(ATP) channel opener sufficient to induce either beta-cell rest orimproved insulin sensitivity or both. Such beta-cell rest andimprovements in insulin sensitivity can contribute to effectivetreatment of type I diabetes, type II diabetes and prediabetes. Suchbeta-cell rest and improvements in insulin sensitivity can contribute toeffective restoration of normal glucose tolerance in type II diabeticand prediabetic subjects.

The various pharmaceutical K_(ATP) channel opener formulations have avariety of applications, including, but not limited to: (1) treatment ofobesity; (2) prevention of weight gain in individuals who arepredisposed to obesity; (3) treatment of hyperinsulemia orhyperinsulinism; (4) treatment of hypoglycemia; (5) treatment ofhyperlipidemia, (6) treatment of type II diabetes, (7) preservation ofpancreatic function in type I diabetics; (8) treatment of metabolicsyndrome (or syndrome X); (9) prevention of the transition fromprediabetes to diabetes, (10) correction of the defects in insulinsecretion and insulin sensitivity contributing to prediabetes and typeII diabetes, (11) treatment of polycystic ovary syndrome, (12)prevention of ischemic or reperfusion injury, (13) treat weight gain,dyslipidemia, or impairment of glucose tolerance in subjects treatedwith antipsychotics drugs, (14) prevent weight gain, dyslipidemia, orimpairment of glucose tolerance in subjects treated with antipsychoticsdrugs and (15) treatment of any disease where hyperlipidemia,hyperinsulemia, hyperinsulinism, hyperlipidemia, hyperphagia or obesityare contributing factors to the severity or progression of the disease,including but not limited to, Prader-Willi Syndrome, Smith-Magenissyndrome, Froelich's syndrome, Cohen syndrome, Summit Syndrome, Alstrom,Syndrome, Borjesen Syndrome, Bardet-Biedl Syndrome, hyperlipoproteinemiatype I, II, III, and IV, and the like.

In one embodiment, a K_(ATP) channel opener is administered to anoverweight or obese individual as a solid oral dosage once per 24 hours,optionally in combination with growth hormone, to induce weight loss. Infurther embodiments, the individual (a) is not a type I diabetic, (b) isnot a type II diabetic, (c) is not experiencing chronic, recurrent ordrug-induced hypoglycemia, (d) does not have metabolic syndrome, or (e)is not experiencing malignant hypertension.

In one embodiment, a K_(ATP) channel opener is administered to anoverweight or obese individual as a solid oral dosage twice per 24hours, optionally in combination with growth hormone, to induce weightloss. This treatment can be the sole treatment to induce weight loss. Infurther embodiments, the overweight or obese individual (a) does nothave an insulin secreting tumor, (b) is not suffering from Poly CysticOvary Syndrome, (c) is not a type I diabetic, (d) is not a type IIdiabetic, (e) does not have metabolic syndrome, (f) is not experiencingchronic recurrent or drug-induced hypoglycemia, (g) has not been treatedfor schizophrenia with haloperidol, or (h) is not experiencing malignanthypertension. In further embodiments, the overweight or obese adolescent(a) has not been diagnosed as being type I or type II diabetic, (b) isnot experiencing chronic, recurrent or drug-induced hypoglycemia, or (c)has not been diagnosed as having metabolic syndrome.

In another embodiment, a K_(ATP) channel opener is administered to anoverweight or obese individual as a solid oral dosage form three timesper 24 hours, optionally in combination with growth hormone, to induceweight loss. This treatment can be the sole treatment to induce weightloss. In further embodiments, the overweight or obese individual (a)does not have an insulin-secreting tumor, (b) is not suffering from PolyCystic Ovary Syndrome, (c) is not a type I diabetic, (d) is not a typeII diabetic, (e) does not have metabolic syndrome, or (f) is notexperiencing chronic, recurrent or drug-induced hypoglycemia.

In another embodiment, a K_(ATP) channel opener is administered to anoverweight or obese adolescent as a solid oral dosage form three timesper 24 hours, optionally in combination with growth hormone, to induceweight loss. This treatment can be the sole treatment to induce weightloss. In further embodiments, the overweight or obese adolescent is (a)is a type I or type II diabetic, (b) is not experiencing chronic,recurrent or drug-induced hypoglycemia or (c) does not have metabolicsyndrome.

In another embodiment, a K_(ATP) channel opener is administered as asolid oral dosage form three times per 24 hours, optionally incombination with growth hormone, to induce weight loss to an overweightor obese adult who (a) is not simultaneously receiving glucagoninjections, triiodothyroxin or furosemide, (b) is not being treated forschizophrenia with haloperidol, or (c) is not experiencing malignanthypertension.

In another embodiment, a K_(ATP) channel opener is administered to anoverweight or obese individual as a solid oral dosage form four timesper 24 hours, optionally in combination with growth hormone, to induceweight loss.

In another embodiment, a K_(ATP) channel opener is administered to anoverweight or obese individual as a solid oral dosage form administeredfrom one, two, three or four times per 24 hours, optionally incombination with growth hormone, to induce weight loss at a daily doseof 50 to 275 mg. In a further embodiment, the overweight or obeseindividual (a) is not type I diabetic, (b) is not type II diabetic, (c)is not suffering chronic, recurrent or drug-induced hypoglycemia, or (d)does not have metabolic syndrome.

In another embodiment, a K_(ATP) channel opener is administered to anoverweight or obese individual as a solid oral dosage form administeredfrom one, two, three or four times per 24 hours, optionally incombination with growth hormone, to induce weight loss at a daily doseof 130 to 275 mg. In a further embodiment, the overweight or obeseindividual (a) is not type I diabetic, (b) is not type II diabetic, (c)is not suffering chronic, recurrent or drug-induced hypoglycemia, or (d)does not have metabolic syndrome.

In another embodiment, a K_(ATP) channel opener is administered to anoverweight or obesity prone individual as a solid oral dosage form one,two, three or four times per 24 hours, optionally in combination withgrowth hormone, to maintain a weight loss, as it is preferable tomaintain weight in an obese individual once some weight loss hasoccurred when the alternative is to regain weight. In a furtherembodiment, the administered daily dose of the K_(ATP) channel opener is50 to 275 mg.

In other embodiments, a K_(ATP) channel opener is administered as asolid oral dosage form to an overweight, obese, or obesity proneindividual, optionally in combination with growth hormone, to (a)elevate energy expenditure, (b) elevate beta oxidation of fat, or (c)reduce circulating triglyceride concentrations.

In other embodiments, a solid oral dosage of a K_(ATP) channel opener isadministered on a prolonged basis to an individual in need thereof toinduce the loss of 25%, 50%, or 75% of initial body fat.

In another embodiment, a solid oral dosage of a K_(ATP) channel openeris administered on a prolonged basis to an individual in need thereof,optionally in combination with growth hormone, to induce (a) thepreferential loss of body fat or (b) the preferential loss of visceralbody fat.

In additional embodiments, a solid oral dosage of a K_(ATP) channelopener is administered on a prolonged basis one, two or three times per24 hours at daily doses of 50 to 275 mg to an individual, optionally incombination with growth hormone, to (a) induce the loss of 25%, 50% or75% of initial body fat, (b) induce the preferential loss of body fat,or (c) induce the preferential loss of visceral fat.

In another embodiment, a solid oral dosage of a K_(ATP) channel openeris administered to an individual, optionally in combination with growthhormone, to induce the preferential loss of body fat and to inducereduction in circulating triglycerides.

In another embodiment, a solid oral dosage of a K_(ATP) channel openeris co-administered with growth hormone.

In yet another embodiment, a solid oral dosage of a K_(ATP) channelopener is co-administered with growth hormone and optionally one or moreof sibutramine, orlistat, rimonabant, an appetite suppressant, ananti-depressant, an anti-epileptic, a diuretic that is not furosemide, adrug that induces weight loss by a mechanism that is distinct from aK_(ATP) channel opener, a drug that induces weight loss by a mechanismthat is distinct from a K_(ATP) channel opener but is not metformin,furosemide or triiodothyroxin, or a drug that lowers blood pressure, toinduce weight loss and/or treat obesity associated comorbidities in anoverweight, obese, or obesity prone individual. In further embodiments,the overweight, obese, or obesity prone individual (a) is a type Idiabetic, (b) is not a type II diabetic, (c) is not suffering fromchronic, recurrent or drug-induced hypoglycemia, or (d) does not havemetabolic syndrome.

In another embodiment a solid oral dosage of a K_(ATP) channel opener isco-administered with growth hormone and optionally one or more of ananti-depressant, a drug that lowers blood pressure, a drug that lowerscholesterol, a drug that raises HDL, an anti-inflammatory that is not aCox-2 inhibitor, a drug that lowers circulating triglycerides, to anoverweight, obese, or obesity prone individual to induce weight lossand/or treat obesity associated comorbidities. In further embodiments,the overweight, obese, or obesity prone individual (a) is not a type Idiabetic, (b) is not a type II diabetic, (c) is not suffering fromchronic, recurrent or drug-induced hypoglycemia, or (d) does not havemetabolic syndrome.

In another embodiment, a solid oral dosage of a K_(ATP) channel openeris co-administered with growth hormone and optionally one or more of adrug that lowers blood pressure, a drug that lowers cholesterol, a drugthat raises HDL, an anti-inflammatory that is not a Cox-2 inhibitor, adrug that lowers circulating triglycerides, to maintain weight and/ortreat obesity associated comorbidities in an overweight, obese, orobesity prone individual, as it is preferable to maintain weight in anobese individual once some weight loss has occurred when the alternativeis to regain weight. In further embodiments, the overweight, obese, orobesity prone individual (a) is not a type I diabetic, (b) is not a typeII diabetic, (c) is not suffering from chronic, recurrent ordrug-induced hypoglycemia, or (d) does not have metabolic syndrome.

In additional embodiments, a tablet formulation of a K_(ATP) channelopener is used to administer a therapeutically effective dose of aK_(ATP) channel opener to an obese, overweight or obesity proneindividual in need thereof to treat obesity, to (a) provide beta cellrest, (b) treat type I or type II diabetes, or (c) prevent theoccurrence of diabetes.

In additional embodiments, a solid oral dosage form or tabletformulation of a K_(ATP) channel opener is co-administered with growthhormone and optionally one or more of Phentermine or a derivativethereof to an obese adult or adolescent to induce weight loss and/ortreat obesity and obesity-associated co-morbidities. In furtherembodiments, a solid oral dosage form or tablet formulation of a K_(ATP)channel opener is co-administered with Phentermine or a derivative,optionally in combination with growth hormone, thereof to an obese adultor adolescent to treat metabolic syndrome in a patient in need thereof.

In further embodiments, a pharmaceutically acceptable formulation of aK_(ATP) channel opener at doses of 50 to 275 mg/day is co-administeredwith growth hormone and optionally one or more of Phentermine or aderivative thereof at daily doses of 15 to 37.5 mg to an overweight orobese individual to induce weight loss, to treat metabolic syndrome, orto induce weight loss and treat obesity-associated co-morbidities. Inanother embodiment, a tablet formulation is co-administered with growthhormone and optionally one or more of Phentermine or a derivativethereof to treat metabolic syndrome in a patient.

In another embodiment, a quick dissolving formulation of a K_(ATP)channel opener, optionally in combination with growth hormone, is usedto provide a therapeutically effective dose to a patient in needthereof.

In further embodiments, a K_(ATP) channel opener is administered,optionally in combination with growth hormone, once per 24 hours atdoses of 125 mg to 275 mg to an overweight or obese individual who isnot type II diabetic and is not being treated for nighttimehypoglycemia.

In further embodiments, a K_(ATP) channel opener is formulated as atablet or capsule for oral administration. The tablet or capsule may beco-formulated with metformin. In another embodiment, a K_(ATP) channelopener is formulated as an oral suspension, and the oral suspension maybe further encapsulated in another embodiment.

In another embodiment, a pharmaceutical salt of a K_(ATP) channel openeris formulated as a tablet or capsule for oral administration, or as anoral suspension or as an oral solution, or as an oral solution that isencapsulated. If the opener is diazoxide, the salt, is preferably not asodium salt.

In another embodiment a K_(ATP) channel opener is co-formulated withhydrochlorothiazide, chlorothiazide, cyclothiazide, benzthiazide,metyclothiazide, bendroflumethiazide, hydroflumethiazide,trichlormethiazide, or polythiazide in a pharmaceutical formulationsuitable for oral administration.

Upon administration of the formulations provided herein to humans oranimals, some or all of the following effects are observed: (1) theproduction of lipoprotein lipase by adipocytes is reduced; (2) enhancedlipolysis by adipocytes; (3) expression of fatty acid synthase byadipocytes is reduced; (4) glyceraldehydes phosphate dehydrogenaseactivity of adipocytes is reduced; (5) little or no new triglyceridesare synthesized and stored by adipocytes; (6) enhanced expression of β₃Adrenergic Receptor (β₃AR) an improvement in the adrenergic function inadipocytes; (7) reduced glucose stimulated secretion of insulin bypancreatic B-cells; (8) decreased insulinemia; (9) enhanced bloodglucose levels; (10) increased expression of Uncoupling Protein 1 inadipocytes; (11) enhanced thermogenesis in white and brown adiposetissue; (12) reduction of plasma triglyceride concentration; (13)decrease in circulating leptin concentrations; (14) up-regulation ofinsulin receptors; (15) enhanced glucose uptake; (16) reduced adipocytehyperplasia; (17) reduced adipocyte hypertrophy; (18) reduced rates ofconversion of preadipocytes to adipocytes; (19) reduced rates ofhyperphagia, (20) increased protection of CNS, cardiac and other tissuesfrom ischemic or reperfusion injury, (21) improved insulin sensitivity,(22) elevated CSF insulin concentrations, (23) elevated circulatingadiponectin concentrations, (25) reduced circulating triglycerideconcentrations, (26) enhancement of beta-cell rest, and/or (27) increasein lean body mass.

Threshold concentrations of the current invention include thosecirculating concentrations of K_(ATP) channel openers, optionally incombination with growth hormone, resulting from the administration ofthe drug as an i.v. formulation, an immediate release oral formulation,a controlled release formulation, a transdermal formulation, or anintranasal formulation to an overweight or obese individual whichresults in (1) measurable suppression of fasting insulin levels, (2)suppression of fasting insulin levels by at least 20% from the baselinemeasurement in the same individual prior to treatment with a K_(ATP)channel openers, (3) suppression of fasting insulin levels by at least30% from the baseline measurement in the same individual prior totreatment with K_(ATP) channel openers, (4) suppression of fastinginsulin levels by at least 40% from the baseline measurement in the sameindividual prior to treatment with a K_(ATP) channel openers, (5)suppression of fasting insulin levels by at least 50% from the baselinemeasurement in the same individual prior to treatment with K_(ATP)channel openers, (6) suppression of fasting insulin levels by at least60% from the baseline measurement in the same individual prior totreatment with K_(ATP) channel openers, (7) suppression of fastinginsulin levels by at least 70% from the baseline measurement in the sameindividual prior to treatment with K_(ATP) channel openers, (8)suppression of fasting insulin levels by at least 80% from the baselinemeasurement in the same individual prior to treatment with K_(ATP)channel openers, (9) loss of weight, (10) elevation of resting energyexpenditure, or (11) elevation of the oxidation of fat or fatty acids.

Threshold effects of the current invention include those circulatingconcentrations of K_(ATP) channel openers resulting from theadministration of an i.v. formulation of the drug, or an immediaterelease oral formulation of the drug, or a controlled releaseformulation of the drug, or a sustained release formulation, or atransdermal formulation, or an intranasal formulation of the drug to anobesity prone individual which result in (1) the loss of weight, and (2)the maintenance of weight.

Threshold effects of the current invention include those circulatingconcentrations of K_(ATP) channel openers resulting from theadministration of an i.v. formulation of the drug, or an immediaterelease oral formulation of the drug, or a controlled releaseformulation of the drug, or a sustained release formulation, or atransdermal formulation, or an intranasal formulation of the drug to aprediabetic individual which result in prevention of the transition todiabetes.

Threshold effects of the current invention include those circulatingconcentrations of K_(ATP) channel openers resulting from theadministration of an i.v. formulation of the drug, or an immediaterelease oral formulation of the drug, or a controlled releaseformulation of the drug, or a sustained release formulation, or atransdermal formulation, or an intranasal formulation of the drug to aindividual with type 1 diabetes which result in beta cell rest.

The mode of action by which weight is maintained or lost resulting fromthe prolonged administration of K_(ATP) channel openers to overweight,obese or obesity prone individuals as provided herein includes, but isnot limited to one or more of (1) enhanced energy expenditure, (2)enhanced oxidation of fat and fatty acids, (3) the enhancement oflipolysis in adipose tissue, (4) enhanced glucose uptake by tissues,enhanced insulin sensitivity, (5) improved beta adrenergic response, and(6) increase in lean body mass. The mode of action by which weight ismaintained or lost resulting from the prolonged administration ofK_(ATP) channel openers to obese or obesity prone individuals asprovided herein may also include the suppression of appetite.

Prolonged administration of pharmaceutical formulations of K_(ATP)channel openers to overweight or obese humans or animals, optionally incombination with growth hormone, results in substantial and sustainedweight loss including some or all of the following effects: (1)preferential loss of body fat; (2) loss of greater than 25% of initialbody fat mass; (3) loss of greater than 50% of initial body fat mass;(4) loss of greater than 75% of initial body fat mass; (5) significantincrease in resting energy expenditure; (6) increase in the oxidation offat and fatty acids; (7) reduction in blood pressure; (8) production oflipoprotein lipase by adipocytes is reduced; (9) enhanced lipolysis byadipocytes; (10) expression of fatty acid synthase by adipocytes isreduced; (11) glyceraldehydes phosphate dehydrogenase activity ofadipocytes is reduced; (12) little or no new triglycerides aresynthesized and stored by adipocytes; (13) enhanced expression of β₃Adrenergic Receptor (β₃AR) and an improvement in the adrenergic functionin adipocytes; (14) reduced glucose stimulated secretion of insulin bypancreatic B-cells; (15) decreased insulinemia; (16) enhanced bloodglucose levels; (17) increased expression of Uncoupling Protein 1 inadipocytes; (18) enhanced thermogenesis in white and brown adiposetissue; (19) reduction of plasma triglyceride concentration; (20)decrease in circulating leptin concentrations; (21) up-regulation ofinsulin receptors; (22) enhanced glucose uptake; (23) reduced adipocytehyperplasia; (24) reduced adipocyte hypertrophy; (25) reduced rates ofconversion of preadipocytes to adipocytes; (26) reduced rates ofhyperphagia; (27) the sequential loss first of the metabolically mostactive adipose tissue (visceral), followed by the loss of lessmetabolically active adipose tissue, (28) elevation of circulatingadiponectin concentrations, (29) elevation of cerebrospinal fluidinsulin levels, (30) enhanced islet insulin mRNA and insulin content,(31) enhanced metabolic efficiency of insulin, or (32) increase in leanbody mass.

Prolonged administration of formulations of K_(ATP) channel openers,optionally in combination with growth hormone, to obesity prone humansor animals, including individuals who have undergone various types ofbariatric surgery, results in sustained maintenance of weight includingsome or all of the following effects: (1) increased resting energyexpenditure; (2) increase in the oxidation of fat and fatty acids; (3)reduction in blood pressure; (4) production of lipoprotein lipase byadipocytes is reduced; (5) enhanced lipolysis by adipocytes; (6)expression of fatty acid synthase by adipocytes is reduced; (7)glyceraldehyde phosphate dehydrogenase activity of adipocytes isreduced; (8) little or no new triglycerides are synthesized and storedby adipocytes; (9) enhanced expression of β₃ Adrenergic Receptor (β₃AR)and improvement in the adrenergic function in adipocytes; (10) reducedglucose stimulated secretion of insulin by pancreatic B-cells; (11)decreased insulinemia; (12) enhanced blood glucose levels; (13)increased expression of Uncoupling Protein 1 in adipocytes; (14)enhanced thermogenesis in white and brown adipose tissue; (15) reductionof plasma triglyceride concentration; (16) decreased circulating leptinconcentration; (17) up-regulation of insulin receptors; (18) enhancedglucose uptake; (19) reduced adipocyte hyperplasia; (20) reducedadipocyte hypertrophy; (21) reduced rates of conversion of preadipocytesto adipocytes; and (22) reduced rates of hyperphagia, (23) elevatedcirculating adiponectin concentration, (24) elevated cerebrospinal fluidinsulin levels, (25) enhanced islet insulin mRNA and insulin content, or(26) enhanced metabolic efficiency of insulin.

Immediate or prolonged administration of formulations of K_(ATP) channelopeners, optionally in combination with growth hormone, to prediabeticor type I diabetic humans or animals results in the prevention of betacell failure, improved glycemic control, and prevention of thetransition from prediabetes to diabetes including some or all of thefollowing effects: (1) increase in resting energy expenditure; (2)increase in the oxidation of fat and fatty acids; (3) reduction in bloodpressure; (4) production of lipoprotein lipase by adipocytes is reduced;(5) enhanced lipolysis by adipocytes; (6) expression of fatty acidsynthase by adipocytes is reduced; (7) glyceraldehyde phosphatedehydrogenase activity of adipocytes is reduced; (8) little or no newtriglycerides are synthesized and stored by adipocytes; (9) enhancedexpression of β₃ Adrenergic Receptor (β₃AR) and an improvement in theadrenergic function in adipocytes; (10) reduced glucose stimulatedsecretion of insulin by pancreatic B-cells; (11) decreased insulinemia;(12) enhanced blood glucose levels; (13) increased expression ofUncoupling Protein 1 in adipocytes; (14) enhanced thermogenesis in whiteand brown adipose tissue; (15) reduction of plasma triglycerideconcentration; (16) decreased circulating leptin concentrations; (17)up-regulation of insulin receptors; (18) enhanced glucose uptake; (19)reduced adipocyte hyperplasia; (20) reduced adipocyte hypertrophy; (21)reduced rates of conversion of preadipocytes to adipocytes; (22) reducedrates of hyperphagia, (23) elevated circulating adiponectinconcentrations, (24) elevated cerebrospinal fluid insulin levels, (25)enhanced islet insulin mRNA and insulin content, or (26) enhancedmetabolic efficiency of insulin.

Immediate or prolonged administration of formulations of K_(ATP) channelopeners, optionally in combination with growth hormone, to humans oranimals that are at risk for myocardial infarct, or stroke or undergoinga surgical procedure that restores blood flow to heart or brain resultsin improved therapeutic outcomes post-surgically, or following theoccurrence of myocardial infarct or stroke by improving the survival oftissue after blood flow is restored, reduced stunning of tissue, andaltering the nature of the inflammatory responses.

Pharmaceutical formulations as provided herein are designed to be usedin the treatment of obesity, hyperlipidemia, hypertension, weightmaintenance, type I diabetes, prediabetes, type II diabetes, or anycondition where weight loss, reduction in circulating triglycerides orbeta cell rest contributes to therapeutic outcomes provide for a rangeof critical changes in pharmacodynamic and pharmacokinetic responses toadministered doses of K_(ATP) channel openers, optionally in combinationwith growth hormone, which changes include one or more of the following:(1) extending the pharmacodynamic effect of an administered dose togreater than 24 hours as measured by the suppression of insulinsecretion, (2) providing for substantial uptake of the activepharmaceutical ingredient in the small intestine, (3) providing forsubstantial uptake of the active pharmaceutical ingredient in the largeintestine, (4) result in lowered Cmax versus current oral suspension orcapsule products for the same administered dose of active pharmaceuticalingredient, (5) provide for circulating concentrations of unbound activepharmaceutical ingredient above threshold concentrations for 24 or morehours from a single administered dose, and (6) provide for moreconsistent drug absorption by treated individuals as compared toexisting capsule formulations.

Pharmaceutical co-formulations of the current invention designed totreat a range of conditions in humans and animals include thecombination of K_(ATP) channel openers with growth hormone andoptionally one or more of: (1) a diuretic, (2) a drug that lowers bloodpressure, (3) a drug that suppresses appetite, (4) a cannabinoidreceptor antagonist, (5) a drug that suppresses that action of gastriclipases, (6) any drug that is used to induce weight loss, (7) a drugthat lowers cholesterol, (8) a drug that lowers LDL bound cholesterol,(9) a drug that improves insulin sensitivity, (10) a drug that improvesglucose utilization or uptake, (11) a drug that reduces incidence ofatherosclerotic plaque, (12) a drug that reduces inflammation, (13) adrug that is antidepressant, (14) a drug that is an anti-epileptic, or(15) a drug that is an anti-psychotic.

Treatment of humans or animals of the current invention usingpharmaceutical formulations of K_(ATP) channel openers, optionally incombination with growth hormone, result in reduced incidence of adverseside effects including but not limited to edema, fluid retention,reduced rates of excretion of sodium, chloride, and uric acid,hyperglycemia, ketoacidosis, nausea, vomiting, dyspepsia, ileus andheadaches. These reductions in frequency of adverse side effects areachieved by: (1) initiating dosing of individuals at subtherapeuticdoses and in a step wise manner increasing the dose daily until thetherapeutic dose is achieved where the number of days over which thestep up in dose is effected is 2 to 10, (2) use of the lowest effectivedose to achieve the desired therapeutic effect, (3) use of apharmaceutical formulation that delays release of active until gastrictransit is complete, (4) use of a pharmaceutical formulation that delaysrelease of active until gastric transit is complete, (5) use of apharmaceutical formulation that results in lower circulating peak druglevels as compared to an immediate release oral suspension or capsuleformulation for the same administered dose, and (6) optimizing thetiming of administration of dose within the day and relative to meals.

Treatment of patients suffering from Prader-Willi Syndrome,Smith-Magenis syndrome, Froelich's syndrome, Cohen syndrome, SummitSyndrome, Alstrom, Syndrome, Borjesen Syndrome, Bardet-Biedl Syndrome,and hyperlipoproteinemia type I, II, III, and IV with the currentinvention using pharmaceutical formulations of K_(ATP) channel openers,optionally in combination with growth hormone, result in some or all ofthe following therapeutic outcomes: (1) weight loss, (2) reduced ratesof weight gain, (3) inhibition of hyperphagia, (4) reduced incidence ofimpaired glucose tolerance, prediabetes or diabetes, (5) reducedincidence of congestive heart failure, (6) reduced hypertension, and (7)reduced rates of all cause mortality.

Treatment of prediabetic subjects with the current invention usingpharmaceutical formulations of K_(ATP) channel openers, optionally incombination with growth hormone, result in some or all of the followingtherapeutic outcomes: (1) weight loss, (2) restoration of normal glucosetolerance, (3) delayed rates of progression to diabetes, (4) reducedhypertension, and (5) reduced rates of all cause mortality.

Treatment of diabetic subjects with the current invention usingpharmaceutical formulations of K_(ATP) channel openers, optionally incombination with growth hormone, result in some or all of the followingtherapeutic outcomes: (1) weight loss, (2) restoration of normal glucosetolerance, (3) delayed rates of progression of diabetes, (4)improvements in glucose tolerance, (5) reduced hypertension, and (6)reduced rates of all cause mortality.

Co-administration of drugs with formulations of K_(ATP) channel openersin the treatment of diseases of overweight, obese or obesity prone humanand animal subjects involves the co-administration of a pharmaceuticallyacceptable formulation of K_(ATP) channel openers with an acceptableformulation of growth hormone and optionally one or more of: (1)Sibutramine, (2) orlistat, (3) Rimonabant, (4) a drug that is anappetite suppressant, (5) any drug used to induce weight loss in anobese or overweight individual, (6) a non-thiazide diuretic, (7) a drugthat lowers cholesterol, (8) a drug that raises HDL cholesterol, (9) adrug that lowers LDL cholesterol, (10) a drug that lowers bloodpressure, (11) a drug that is an anti-depressant, (12) a drug thatimproves insulin sensitivity, (13) a drug that improves glucoseutilization and uptake (14) a drug that is an anti-epileptic, (15) adrug that is an anti-inflammatory, or (16) a drug that lowerscirculating triglycerides.

Co-administration of drugs with formulations of K_(ATP) channel openersin the treatment or prevention of weight gain, dyslipidemia, or impairedglucose tolerance in subjects treated with antipsychotics drugs involvethe co-administration of a pharmaceutically acceptable formulation ofK_(ATP) channel openers with growth hormone and optionally one or moreof an acceptable formulation of: lithium, carbamazepine, valproic acidand divalproex, and lamotrigine, antidepressants generally classified asmonoamine oxidase inhibitors including isocarboxazid, phenelzine sulfateand tranylcypromine sulfate, tricyclic antidepressants includingdoxepin, clomipramine, amitriptyline, maproiline, desipromine,nortryptyline, desipramine, doxepin, trimipramine, imipramine andprotryptyline, tetracyclic antidepressants including mianserin,mirtazapine, maprotiline, oxaprotline, delequamine, levoprotline,triflucarbine, setiptiline, lortalaline, azipramine, aptazapine maleateand pirlindole, and major tranquilizers and atypical antipsychoticsincluding paloproxidol, perphenazine, thioridazine, risperidone,clozapine, olanzapine and chlorpromazine.

In one embodiment, a K_(ATP) channel opener, optionally in combinationwith growth hormone, is administered to an overweight or obeseindividual as an oral suspension, or an immediate release capsule ortablet or a controlled release formulation or a transdermal formulationor an intranasal formulation to reach and maintain the thresholdconcentration required to measurably reduce fasting insulin levels for aprolonged period. Preferably the K_(ATP) channel opener formulationreduces fasting insulin levels by at least 20%, more preferably by atleast 30%, more preferably by at least by 40%, more preferably by atleast 50%, more preferably by at least by 60% more preferably by atleast by 70%, and more preferably by at least 80%. Fasting insulinlevels are commonly measured using the glucose tolerance test (OGTT).After an overnight fast, a patient ingests a known amount of glucose.Initial glucose levels are determined by measuring pre-test glucoselevels in blood and urine. Blood insulin levels are measured by a bloodis draw every hour after the glucose is consumed for up to three hours.In a fasting glucose assay individuals with plasma glucose valuesgreater than 200 mg/dl at 2 hours post-glucose load indicate an impairedglucose tolerance.

In another embodiment, a K_(ATP) channel opener, optionally incombination with growth hormone, is administered to an overweight orobese individual as an oral suspension, or an immediate release capsuleor tablet or a controlled release formulation or a transdermalformulation or an intranasal formulation to reach and maintain thethreshold concentration required to induce weight loss for a prolongedperiod.

In another embodiment, a K_(ATP) channel opener, optionally incombination with growth hormone, is administered to an overweight orobese individual as an oral suspension, or an immediate release capsuleor tablet or a controlled release formulation or a transdermalformulation or an intranasal formulation to reach and maintain thethreshold concentration required to elevate resting energy expenditurefor a prolonged period.

In another embodiment, a K_(ATP) channel opener, optionally incombination with growth hormone, is administered to an overweight orobese individual as an oral suspension, or an immediate release capsuleor tablet or a controlled release formulation or a transdermalformulation or an intranasal formulation to reach and maintain thethreshold concentration required to elevate fat and fatty acid oxidationfor a prolonged period.

In another embodiment, a K_(ATP) channel opener, optionally incombination with growth hormone, is administered to an obesity proneindividual as an oral suspension, or an immediate release capsule ortablet or a controlled release formulation or a transdermal formulationor an intranasal formulation to reach and maintain the thresholdconcentration required to induce weight loss for a prolonged period.

In another embodiment, a K_(ATP) channel opener, optionally incombination with growth hormone, is administered to an obesity proneindividual as an oral suspension, or an immediate release capsule ortablet or a controlled release formulation or a transdermal formulationor an intranasal formulation to reach and maintain the thresholdconcentration required to maintain weight for a prolonged period.

In another embodiment, a K_(ATP) channel opener, optionally incombination with growth hormone, is administered to an overweight orobese individual as an oral suspension, or an immediate release capsuleor tablet or a controlled release formulation or a transdermalformulation or an intranasal formulation to reach and maintain a drugconcentration above the threshold concentration required to induceweight loss for a prolonged period.

In another embodiment, a K_(ATP) channel opener, optionally incombination with growth hormone, is administered to an overweight orobese individual as an oral suspension, or an immediate release capsuleor tablet or a controlled release formulation or a transdermalformulation or an intranasal formulation for a prolonged period of timeto reduce body fat by more than 25%, more preferably by at least 50%,and more preferably by at least 75%.

In another embodiment, a K_(ATP) channel opener, optionally incombination with growth hormone, is administered to an overweight orobese individual as an oral suspension, or an immediate release capsuleor tablet or a controlled release formulation or a transdermalformulation or an intranasal formulation for a prolonged period of timeto preferentially reduce visceral fat deposits.

In another embodiment, a K_(ATP) channel opener, optionally incombination with growth hormone, is administered to an overweight orobese individual as an oral suspension, or an immediate release capsuleor tablet or a controlled release formulation or a transdermalformulation or an intranasal formulation for a prolonged period of timeto reduce visceral fat depots and other fat deposits.

In another embodiment, a K_(ATP) channel opener, optionally incombination with growth hormone, is administered to a normoinsulemicoverweight or obese individual as an oral suspension, or an immediaterelease capsule or tablet or a controlled release formulation or atransdermal formulation or an intranasal formulation to reach andmaintain a drug concentration above the threshold concentration requiredto induce weight loss for a prolonged period.

In another embodiment, a K_(ATP) channel opener, optionally incombination with growth hormone, is administered to a prediabeticindividual as an oral suspension, or an immediate release capsule ortablet or a controlled release formulation or a transdermal formulationor an intranasal formulation to reach and maintain a drug concentrationabove the threshold concentration required to prevent the transition todiabetes for a prolonged period.

In another embodiment, a K_(ATP) channel opener, optionally incombination with growth hormone, is administered to a type 1 diabeticindividual as an oral suspension, or an immediate release capsule ortablet or a controlled release formulation or a transdermal formulationor an intranasal formulation to reach and maintain a drug concentrationabove the threshold concentration required to induce beta cell rest fora prolonged period.

In another embodiment, a single dose of a pharmaceutically acceptableformulation of a K_(ATP) channel opener, optionally in combination withgrowth hormone, is administered to an individual in need thereof thatresults in circulating concentration of active drug sufficient todiminish the secretion of insulin for 24 or more hours.

In another embodiment, a pharmaceutically acceptable formulation of aK_(ATP) channel opener, optionally in combination with growth hormone,is administered over a prolonged basis to an individual in need thereofno more than once per 24 hours that results in circulating concentrationof active drug sufficient to diminish the secretion of insulin on acontinuous basis.

In another embodiment, a single dose of a pharmaceutically acceptableformulation of a K_(ATP) channel opener, optionally in combination withgrowth hormone, is administered to an individual in need thereof thatresults in circulating concentration of active drug sufficient toelevate non-esterified fatty acids in circulation for 24 or more hours.

In another embodiment, a pharmaceutically acceptable formulation of aK_(ATP) channel opener, optionally in combination with growth hormone,is administered over a prolonged basis to an individual in need thereofno more than once per 24 hours that results in circulating concentrationof active drug sufficient to elevate non-esterified fatty acids incirculation on a continuous basis.

In another embodiment, a single dose of a pharmaceutically acceptableformulation of a K_(ATP) channel opener, optionally in combination withgrowth hormone, is administered to an individual in need thereof thatresults in circulating concentration of active drug sufficient to treathypoglycemia in circulation for 24 or more hours.

In another embodiment, a pharmaceutically acceptable formulation of aK_(ATP) channel opener, optionally in combination with growth hormone,is administered over a prolonged basis to an individual in need thereofno more than once per 24 hours that results in circulating concentrationof active drug sufficient to treat hypoglycemia on a continuous basis.

In another embodiment, a pharmaceutically acceptable formulation of aK_(ATP) channel opener, optionally in combination with growth hormone,is administered over a prolonged basis to an individual in need thereofno more than once per 24 hours that results in circulating concentrationof active drug sufficient to induce weight loss on a continuous basis.

In another embodiment, a pharmaceutically acceptable formulation of aK_(ATP) channel opener, optionally in combination with growth hormone,is administered over a prolonged basis to an individual in need thereofno more than once per 24 hours that results in circulating concentrationof active drug sufficient to maintain weight on a continuous basis, asit is preferable to maintain weight in an obese individual once someweight loss has occurred when the alternative is to regain weight.

In another embodiment, a pharmaceutically acceptable formulation of aK_(ATP) channel opener, optionally in combination with growth hormone,is administered over a prolonged basis to an individual in need thereofno more than once per 24 hours that results in circulating concentrationof active drug sufficient to reduce circulating triglyceride levels on acontinuous basis.

In another embodiment, a single dose of a pharmaceutically acceptableformulation of a K_(ATP) channel opener, optionally in combination withgrowth hormone, is administered to an individual in need thereof thatresults in circulating concentration of active drug sufficient to reduceor prevent ischemic or reperfusion injury in circulation for 24 or morehours.

In another embodiment, a pharmaceutically acceptable formulation of aK_(ATP) channel opener, optionally in combination with growth hormone,is administered over a prolonged basis to an individual in need thereofno more than once per 24 hours that results in circulating concentrationof active drug sufficient reduce or prevent ischemic or reperfusioninjury on a continuous basis.

In another embodiment, the adverse effects of frequent treatment with aK_(ATP) channel opener, optionally in combination with growth hormone,is reduced using a pharmaceutically acceptable formulation of diazoxideor its derivatives that is administered to an individual in need thereofon a daily basis in which the first dose is known to be subtherapeuticand daily dose is subsequently increased stepwise until the therapeuticdose is reached.

In another embodiment, the adverse effects of frequent treatment with aK_(ATP) channel opener, optionally in combination with growth hormone,is reduced using a pharmaceutically acceptable formulation of a K_(ATP)channel opener that is administered to an individual in need thereof ona daily basis in which the active ingredient is not released from theformulation until gastric transit is complete.

In another embodiment, the adverse effects of frequent treatment with aK_(ATP) channel opener, optionally in combination with growth hormone,is reduced using a pharmaceutically acceptable formulation of a K_(ATP)channel opener that is administered to an individual in need thereof ona daily basis in which the active ingredient is not released from theformulation until gastric transit is complete.

In another embodiment, the adverse effects of frequent treatment with aK_(ATP) channel opener, optionally in combination with growth hormone,is reduced using a pharmaceutically acceptable formulation of a K_(ATP)channel opener, optionally in combination with growth hormone, that isadministered to an individual in need thereof on a daily basis in whichthe maximum circulating concentration of active ingredient is lower thanwhat would be realized by the administration of the same dose using anoral suspension or capsule formulation.

In another embodiment, the adverse effects of frequent treatment with aK_(ATP) channel opener, optionally in combination with growth hormone,is reduced using a pharmaceutically acceptable formulation of a K_(ATP)channel opener, optionally in combination with growth hormone, that isadministered to an individual in need thereof on a daily basis in whichthe first dose is known to be subtherapeutic and daily dose issubsequently increased stepwise until the therapeutic dose is reached,the active ingredient is not released from the formulation until gastrictransit is complete and in which the maximum circulating concentrationof active ingredient is lower than what would be realized by theadministration of the same dose using an oral suspension or capsuleformulation.

In another embodiment, the adverse effects of frequent treatment with aK_(ATP) channel opener, optionally in combination with growth hormone,is reduced using a pharmaceutically acceptable formulation of a K_(ATP)channel opener, optionally in combination with growth hormone, that isadministered to an overweight or obese individual in need thereof on adaily basis in which the first dose is known to be subtherapeutic anddaily dose is subsequently increased stepwise until the therapeutic doseis reached, the active ingredient is not released from the formulationuntil gastric transit is complete, in which the maximum circulatingconcentration of active ingredient is lower than what would be realizedby the administration of the same dose using an oral suspension orcapsule formulation, and in which the maximum dose is less than 2.5mg/kg/day.

In another embodiment, the adverse effects of frequent treatment with aK_(ATP) channel opener, optionally in combination with growth hormone,is reduced using a pharmaceutically acceptable formulation of a K_(ATP)channel opener, optionally in combination with growth hormone, that isadministered to an overweight or obese individual in need thereof on adaily basis in which the first dose is known to be subtherapeutic anddaily dose is subsequently increased stepwise until the therapeutic doseis reached, the active ingredient is not released from the formulationuntil gastric transit is complete, in which the maximum circulatingconcentration of active ingredient is lower than what would be realizedby the administration of the same dose using an oral suspension orcapsule formulation, and in which the maximum dose is less than 1.75mg/kg/day.

In another embodiment, the treatment of an overweight or obeseindividual is optimized for weight loss by administration of apharmaceutically acceptable formulation of a K_(ATP) channel opener,optionally in combination with growth hormone, once per 24 hours inwhich the release of the active ingredient from the formulation has beenmodified to provide near zero order release for at least 12 hours.

In another embodiment, the treatment of an overweight or obeseindividual is optimized for weight loss by administration of apharmaceutically acceptable formulation of a K_(ATP) channel opener,optionally in combination with growth hormone, once per 24 hours inwhich the release of the active ingredient from the formulation has beenmodified to provide near zero order release for at least 18 hours.

In another embodiment, the treatment of an overweight or obeseindividual is optimized for weight loss by administration of apharmaceutically acceptable formulation of a K_(ATP) channel opener,optionally in combination with growth hormone, once per 24 hours inwhich the release of the active ingredient from the formulation has beenmodified to provide a rising drug concentration in circulation for atleast 12 hours.

In another embodiment, the treatment of an overweight or obeseindividual is optimized for weight loss by administration of apharmaceutically acceptable formulation of a K_(ATP) channel opener,optionally in combination with growth hormone, once per 24 hours inwhich the release of the active ingredient from the formulation has beenmodified to provide a rising drug concentration in circulation for atleast 18 hours.

In another embodiment, the treatment of an overweight or obeseindividual is optimized for weight loss by administration of apharmaceutically acceptable formulation of a K_(ATP) channel opener,optionally in combination with growth hormone, once per 24 hours inwhich the release of the active ingredient from the formulation has beenmodified to match the pattern of basal insulin secretion.

In another embodiment, the frequency of adverse effects upon treatmentwith a K_(ATP) channel opener is reduced using a pharmaceuticallyacceptable formulation of a K_(ATP) channel opener, optionally incombination with growth hormone, that is administered to an obesityprone individual in need thereof on a daily basis in which the firstdose is known to be subtherapeutic and daily dose is subsequentlyincreased stepwise until the therapeutic dose is reached, the activeingredient is not released from the formulation until gastric transit iscomplete, in which the maximum circulating concentration of activeingredient is lower than what would be realized by the administration ofthe same dose using an oral suspension or capsule formulation, and inwhich the maximum dose is less than 2.5 mg/kg/day.

In another embodiment, the frequency of adverse effects upon treatmentwith a K_(ATP) channel opener, optionally in combination with growthhormone, is reduced using a pharmaceutically acceptable formulation of aK_(ATP) channel opener, optionally in combination with growth hormone,that is administered to an obesity prone individual in need thereof on adaily basis in which the first dose is known to be subtherapeutic anddaily dose is subsequently increased stepwise until the therapeutic doseis reached, the active ingredient is not released from the formulationuntil gastric transit is complete, in which the maximum circulatingconcentration of active ingredient is lower than what would be realizedby the administration of the same dose using an oral suspension orcapsule formulation, and in which the maximum dose is less than 1.75mg/kg/day.

In another embodiment, the treatment of an obesity prone individual isoptimized for weight maintenance by administration of a pharmaceuticallyacceptable formulation of a K_(ATP) channel opener, optionally incombination with growth hormone, once per 24 hours in which the releaseof the active ingredient from the formulation has been modified toprovide near zero order release for at least 12 hours.

In another embodiment, the treatment of an obesity prone individual isoptimized for weight maintenance by administration of a pharmaceuticallyacceptable formulation of a K_(ATP) channel opener, optionally incombination with growth hormone, once per 24 hours in which the releaseof the active ingredient from the formulation has been modified toprovide near zero order release for at least 18 hours.

In another embodiment, the treatment of an obesity prone individual isoptimized for weight maintenance by administration of a pharmaceuticallyacceptable formulation of a K_(ATP) channel opener, optionally incombination with growth hormone, once per 24 hours in which the releaseof the active ingredient from the formulation has been modified toprovide a rising drug concentration in circulation for at least 12hours.

In another embodiment, the treatment of an obesity prone individual isoptimized for weight maintenance by administration of a pharmaceuticallyacceptable formulation of a K_(ATP) channel opener, optionally incombination with growth hormone, once per 24 hours in which the releaseof the active ingredient from the formulation has been modified toprovide a rising drug concentration in circulation for at least 18hours.

In another embodiment, the treatment of an obesity prone individual isoptimized for weight maintenance by administration of a pharmaceuticallyacceptable formulation of a K_(ATP) channel opener, optionally incombination with growth hormone, once per 24 hours in which the releaseof the active ingredient from the formulation has been modified to matchthe pattern of basal insulin secretion.

In another embodiment, a pharmaceutically acceptable formulation of aK_(ATP) channel opener, optionally in combination with growth hormone,is co-administered with sibutramine to an overweight or obese individualto induce weight loss.

In another embodiment, a pharmaceutically acceptable formulation of aK_(ATP) channel opener, optionally in combination with growth hormone,is co-administered with orlistat to an overweight or obese individual toinduce weight loss.

In another embodiment, a pharmaceutically acceptable formulation of aK_(ATP) channel opener, optionally in combination with growth hormone,is co-administered with rimonabant to an overweight or obese individualto induce weight loss.

In another embodiment, a pharmaceutically acceptable formulation of aK_(ATP) channel opener, optionally in combination with growth hormone,is co-administered with an appetite suppressant to an overweight orobese individual to induce weight loss.

In another embodiment, a pharmaceutically acceptable formulation of aK_(ATP) channel opener, optionally in combination with growth hormone,is co-administered with an anti-depressant to an overweight or obeseindividual to induce weight loss.

In another embodiment, a pharmaceutically acceptable formulation of aK_(ATP) channel opener, optionally in combination with growth hormone,is co-administered with anti-epileptic to an overweight or obeseindividual to induce weight loss.

In another embodiment, a pharmaceutically acceptable formulation of aK_(ATP) channel opener, optionally in combination with growth hormone,is co-administered with a non-thiazide diuretic to an overweight orobese individual to induce weight loss.

In another embodiment, a pharmaceutically acceptable formulation of aK_(ATP) channel opener, optionally in combination with growth hormone,is co-administered with a drug that induces weight loss by a mechanismthat is distinct from diazoxide to an overweight or obese individual toinduce weight loss.

In another embodiment, a pharmaceutically acceptable formulation of aK_(ATP) channel opener, optionally in combination with growth hormone,is co-administered with a drug that lowers blood pressure to anoverweight, obesity prone or obese individual to induce weight loss andtreat obesity associated comorbidities.

In another embodiment, a pharmaceutically acceptable formulation of aK_(ATP) channel opener, optionally in combination with growth hormone,is co-administered with a drug that lowers cholesterol to an overweight,obesity prone or obese individual to induce weight loss and treatobesity associated comorbidities.

In another embodiment, a pharmaceutically acceptable formulation of aK_(ATP) channel opener, optionally in combination with growth hormone,is co-administered with a drug that raises HDL associated cholesterol toan overweight, obesity prone or obese individual to induce weight lossand treat obesity associated comorbidities.

In another embodiment, a pharmaceutically acceptable formulation of aK_(ATP) channel opener, optionally in combination with growth hormone,is co-administered with a drug that improves insulin sensitivity to anoverweight, obesity prone or obese individual to induce weight loss andtreat obesity associated comorbidities.

In another embodiment, a pharmaceutically acceptable formulation of aK_(ATP) channel opener, optionally in combination with growth hormone,is co-administered with an anti-inflammatory to an overweight, obesityprone or obese individual to induce weight loss and treat obesityassociated comorbidities.

In another embodiment, a pharmaceutically acceptable formulation of aK_(ATP) channel opener, optionally in combination with growth hormone,is co-administered with a drug that lowers circulating triglycerides toan overweight, obesity prone or obese individual to induce weight lossand treat obesity associated comorbidities.

In another embodiment, K_(ATP) channel openers, optionally incombination with growth hormone, are co-formulated with sibutramine in apharmaceutically acceptable formulation that is administered to anoverweight, obesity prone or obese individual to induce weight loss andtreat obesity-associated co-morbidities.

In another embodiment, K_(ATP) channel openers, optionally incombination with growth hormone, are co-formulated with orlistat orother active that suppresses the action of gastric lipases in apharmaceutically acceptable formulation that is administered to anoverweight, obesity prone or obese individual to induce weight loss andtreat obesity-associated co-morbidities.

In another embodiment, K_(ATP) channel openers, optionally incombination with growth hormone, are co-formulated with a non-thiazidediuretic in a pharmaceutically acceptable formulation that isadministered to an overweight, obesity prone or obese individual toinduce weight loss and treat obesity-associated co-morbidities.

In another embodiment, K_(ATP) channel openers, optionally incombination with growth hormone, are co-formulated with an appetitesuppressant in a pharmaceutically acceptable formulation that isadministered to an overweight, obesity prone or obese individual toinduce weight loss and treat obesity-associated co-morbidities.

In another embodiment, K_(ATP) channel openers, optionally incombination with growth hormone, are co-formulated with a cannabinoidreceptor antagonist in a pharmaceutically acceptable formulation that isadministered to an overweight, obesity prone or obese individual toinduce weight loss and treat obesity-associated co-morbidities.

In another embodiment, K_(ATP) channel openers, optionally incombination with growth hormone, are co-formulated with ananti-cholesteremic active in a pharmaceutically acceptable formulationthat is administered to an overweight, obesity prone or obese individualto induce weight loss and treat obesity-associated co-morbidities.

In another embodiment, K_(ATP) channel openers, optionally incombination with growth hormone, are co-formulated with anantihypertensive active in a pharmaceutically acceptable formulationthat is administered to an overweight, obesity prone or obese individualto induce weight loss and treat obesity-associated co-morbidities

In another embodiment, K_(ATP) channel openers, optionally incombination with growth hormone, are co-formulated with an insulinsensitizing active in a pharmaceutically acceptable formulation that isadministered to an overweight, obesity prone or obese individual toinduce weight loss and treat obesity-associated co-morbidities.

In another embodiment, K_(ATP) channel openers, optionally incombination with growth hormone, are co-formulated with ananti-inflammatory active in a pharmaceutically acceptable formulationthat is administered to an overweight, obesity prone or obese individualto induce weight loss and treat obesity-associated co-morbidities.

In another embodiment, K_(ATP) channel openers, optionally incombination with growth hormone, are co-formulated with ananti-depressant active in a pharmaceutically acceptable formulation thatis administered to an overweight, obesity prone or obese individual toinduce weight loss and treat obesity-associated co-morbidities.

In another embodiment, K_(ATP) channel openers, optionally incombination with growth hormone, are co-formulated with ananti-epileptic active in a pharmaceutically acceptable formulation thatis administered to an overweight, obesity prone or obese individual toinduce weight loss and treat obesity-associated co-morbidities.

In another embodiment, K_(ATP) channel openers, optionally incombination with growth hormone, are co-formulated with an active thatreduces the incidence of atherosclerotic plaque in a pharmaceuticallyacceptable formulation that is administered to an overweight, obesityprone or obese individual to induce weight loss and treatobesity-associated co-morbidities.

In another embodiment, K_(ATP) channel openers, optionally incombination with growth hormone, are co-formulated with an active thatlowers circulating concentrations of triglycerides in a pharmaceuticallyacceptable formulation that is administered to an overweight, obesityprone or obese individual to induce weight loss and treatobesity-associated co-morbidities.

The reduction of circulating triglycerides in an overweight, obese orobesity prone individual is achieved by the administration of aneffective amount of a solid oral dosage form of a K_(ATP) channelopener, optionally in combination with growth hormone.

A solid oral dosage form of K_(ATP) channel opener can be used toadminister a therapeutically effective dose of K_(ATP) channel opener toan overweight or obesity prone individual in need thereof to maintainweight, as it is preferable to maintain weight in an obese individualonce some weight loss has occurred when the alternative is to regainweight.

A method of inducing loss of greater than 25% of initial body fat in anoverweight or obese individual can be achieved by the prolongedadministration of a solid oral dosage form of a K_(ATP) channel opener,optionally in combination with growth hormone.

A method of inducing loss of greater than 50% of initial body fat in anoverweight or obese individual can be achieved by the prolongedadministration of a solid oral dosage form of a K_(ATP) channel opener,optionally in combination with growth hormone.

A method of inducing loss of greater than 75% of initial body fat in anoverweight or obese individual can be achieved by the prolongedadministration of a solid oral dosage form of a K_(ATP) channel opener,optionally in combination with growth hormone.

A method of inducing preferential loss of visceral fat in an overweightor obese individual can be achieved by the prolonged administration of asolid oral dosage form of a K_(ATP) channel opener, optionally incombination with growth hormone.

A method of inducing loss of body fat and reductions in circulatingtriglycerides in an overweight or obese individual can be achieved bythe prolonged administration of a solid oral dosage form of a K_(ATP)channel opener, optionally in combination with growth hormone.

The invention will now be described with reference to the followingnon-limiting examples.

EXAMPLES Example 1: Potassium ATP Channel Activator ContainingFormulations

1. Compressed Tablet Formulations

Diazoxide or a derivative thereof at about 15-30% by weight is mixedwith hydroxypropyl methylcellulose at about 55-80% by weight,ethylcellulose at about 3-10 wt/vol % and magnesium stearate (aslubricant) and talc (as glidant) each at less than 3% by weight. Themixture is used to produce a compressed tablet as described in Reddy etal., AAPS Pharm Sci Tech 4(4):1-9 (2003). The tablet may be coated witha thin film as discussed below for microparticles.

A tablet containing 100 mg of diazoxide or a derivative thereof willalso contain approximately 400 mg of hydroxypropyl cellulose and 10 mgof ethylcellulose. A tablet containing 50 mg of diazoxide or aderivative thereof will also contain approximately 200 mg ofhydroxypropyl cellulose and 5 mg of ethylcellulose. A tablet containing25 mg of diazoxide or a derivative thereof will also containapproximately 100 mg of hydroxypropyl cellulose and 2.5 mg ofethylcellulose.

2. Encapsulated Coated Microparticle Formulation of Diazoxide

Diazoxide or a derivative thereof is encapsulated into microparticles inaccordance with well known methods (see, e.g. U.S. Pat. No. 6,022,562).Microparticles of between 100 and 500 microns in diameter containingdiazoxide or derivative, alone or in combination with one or moresuitable excipient, is formed with the assistance of a granulator andthen sieved to separate microparticles having the appropriate size.Micriparticles are coated with a thin film by spray drying usingcommercial instrumentation (e.g. Uniglatt Spray Coating Machine). Thethin film comprises ethylcellulose, cellulose acetate,polyvinylpyrrolidone and/or polyacrylamide. The coating solution for thethin film may include a plasticizer which may be castor oil, diethylphthalate, triethyl citrate and salicylic acid. The coating solution mayalso include a lubricating agent which may be magnesium stearate, sodiumoleate, or polyoxyethylenated sorbitan laurate. The coating solution mayfurther include an excipient such as talc, colloidal silica or of amixture of the two added at 1.5 to 3% by weight to prevent caking of thefilm coated particles.

3. Formulation of a Tableted Form of Diazoxide or a Derivative forControlled Release

Prior to mixing, both the active ingredient and hydroxypropylmethylcellulose (Dow Methocel K4M P) are passed through an ASTM 80 meshsieve. A mixture is formed from 1 part diazoxide or a derivative thereofto 4 parts hydroxypropyl methylcellulose. After thorough mixing, asufficient volume of an ethanolic solution of ethylcellulose as agranulating agent is added slowly. The quantity of ethylcellulose pertablet in the final formulation is about 1/10th part. The mass resultingfrom mixing the granulating agent is sieved through 22/44 mesh.Resulting granules are dried at 40° C. for 12 hours and thereafter keptin a desiccator for 12 hours at room temperature. Once dry the granulesretained on 44 mesh are mixed with 15% fines (granules that passedthrough 44 mesh). Talc and magnesium stearate are added as glidant andlubricant at 2% of weight each. A colorant is also added. The tabletsare compressed using a single punch tablet compression machine.

4. Formulation of a Compression Tableted Form of Diazoxide or aDerivative Thereof that Provides for Controlled Release

Diazoxide or a derivative thereof at 20-40% weight is mixed with 30%weight hydroxypropyl methylcellulose (Dow Methocel K100LV P) and 20-40%weight impalpable lactose. The mixture is granulated with the additionof water. The granulated mixture is wet milled and then dried 12 hoursat 110° C. The dried mixture is dry milled. Following milling, 25%weight ethylcellulose resin is added (Dow Ethocel 10FP or Ethocel 100FP)followed by 0.5% weight magnesium stearate. A colorant is also added.The tablets are compressed using a single punch tablet compressionmachine (Dasbach, et al, Poster at AAPS Annual Meeting Nov. 10-14(2002)).

5. Formulation of a Compression Coated Tableted Form of Diazoxide or aDerivative Thereof that Provides for Controlled Release.

The core tablet is formulated by mixing either 100 mg of diazoxide or aderivative thereof with 10 mg of ethylcellulose (Dow Ethocel 10FP), orby mixing 75 mg of diazoxide or a derivative thereof with 25 mg lactoseand 10 mg of ethylcellulose (Dow Ethocel 10FP), or by mixing 50 mg ofdiazoxide or a derivative thereof with 50 mg of lactose and 10 mg ofethylcellulose (Dow Ethocel 10FP). The core tablets are formed on anautomated press with concave tooling. The compression coating consistingof 400 mg of ethylene oxide (Union Carbide POLYOX WSR Coagulant) isapplied and compressed to 3000 psi (Dasbach, et al., Poster at AAPSAnnual Meeting Oct. 26-30 (2003)).

6. A Controlled Release Dosage Form of Diazoxide or a Derivative ThereofUsing an Osmotically Controlled Release System

Diazoxide or a derivative thereof is formulated as an osmoticallyregulated release system. In general, two components, and expandablehydrogel that drives release of the active drug is assembled withdiazoxide or a derivative thereof into a semipermeable bilaminate shell.Upon assembly a hole is drilled in the shell to facilitate release ofactive upon hydration of the hydrogel.

A dosage form adapted, designed and shaped as an osmotic delivery systemis manufactured as follows: first, a diazoxide or a derivative thereofcomposition is provided by blending together into a homogeneous blend ofpolyethylene oxide, of diazoxide or a derivative thereof andhydroxypropyl methylcellulose. Then, a volume of denatured anhydrousethanol weighing 70% of the dry mass is added slowly with continuousmixing over 5 minutes. The freshly prepared wet granulation is screenedthrough a 20 mesh screen through a 20 mesh screen, dried at roomtemperature for 16 hours, and again screened through a 20 mesh screen.Finally, the screened granulation is mixed with 0.5% weight of magnesiumstearate for 5 minutes.

A hydrogel composition is prepared as follows: first, 69% weight ofpolyethylene oxide weight, 25% weight of sodium chloride and 1% weightferric oxide separately are screened through a 40 mesh screen. Then, allthe screened ingredients are mixed with 5% weight of hydroxypropylmethylcellulose to produce a homogeneous blend. Next, a volume ofdenatured anhydrous alcohol equal to 50% of the dry mass is added slowlyto the blend with continuous mixing for 5 minutes. The freshly preparedwet granulation is passed through a 20 mesh screen, allowed to dry atroom temperature for 16 hours, and again passed through a 20 meshscreen. The screened granulation is mixed with 0.5% weight of magnesiumstearate 5 minutes (see U.S. Pat. No. 6,361,795 by Kuczynski, et al.).

The diazoxide or a derivative thereof composition and the hydrogelcomposition are compressed into bilaminate tablets. First the diazoxideor a derivative thereof composition is added and tamped, then, thehydrogel composition is added and the laminae are pressed under apressure head of 2 tons into a contacting laminated arrangement.

The bilaminate arrangements are coated with a semipermeable wall (i.e.thin film). The wall forming composition comprises 93% cellulose acetatehaving a 39.8% acetyl content, and 7% polyethylene glycol. The wallforming composition is sprayed onto and around the bilaminate.

Finally an exit passageway is drilled through the semipermeable wall toconnect the diazoxide or a derivative thereof drug lamina with theexterior of the dosage system. The residual solvent is removed by dryingat 50° C. and 50% humidity. Next, the osmotic systems are dried at 50°C. to remove excess moisture (see U.S. Pat. No. 6,361,795 by Kuczynski,et al.).

7. Preparation of a Salt of Diazoxide

A hydrochloride salt of diazoxide is prepared by dissolving one mole ofdiazoxide (230.7 g) in 500 ml of Et₂O. Dry HCl is passed into thesolution until the weight of the container is increased by 36 g. Duringthe addition of the HCl, the HCl salt of diazoxide precipitates as apowder. The salt is filtered off and washed with dry Et₂O.

Example 2: In Vivo Obesity Testing

1. Obesity Animal Model

Formulations of diazoxide or derivatives prepared as described hereincan be tested for efficacy in an animal model of obesity as described bySurwit et al. (Endocrinology 141:3630-3637 (2000)). Briefly, 4-week-oldB6 male mice are housed 5/cage in a temperature-controlled (22° C.) roomwith a 12-h light, 12-h dark cycle. The high fat (HF) and low fat (LF)experimental diets contain 58% and 11% of calories from fat,respectively. A group of mice are fed the HF diet for the first 4 weeksof the study; the remaining 15 mice are fed the LF diet. The miceassigned to the LF diet are maintained on this diet throughout the studyas a reference group of lean control mice. At week 4, all HF-fed mice areassigned to 2 groups of mice. The first group remains on the HF dietthroughout the study as the obese control group. The remaining 3 groupsof mice are fed the HF diet and administered the controlled releaseformulation of diazoxide or derivative at about 150 mg of active per kgper day as a single dose administered by oral gavage. Animals areweighed weekly, and food consumption is measured per cage twice weeklyuntil the diets are changed at week 4, whereupon body weight and foodintake are determined daily. The feed efficiency (grams of body weightgained per Cal consumed) is calculated on a per cage basis. Samples foranalysis of insulin, glucose, and leptin are collected on day 24 (4 daysbefore the diets are changed), on day 32 (4 days after the change), andbiweekly thereafter. In all cases food is removed 8 h before samples arecollected. Glucose is analyzed by the glucose oxidase method. Insulinand leptin concentrations are determined by double antibody RIA. Theinsulin assay is based on a rat standard, and the leptin assay uses amouse standard. At the termination of the study, a postprandial plasmasample is collected and analyzed for triglyceride and nonesterifiedfatty acid concentrations. After 4 weeks of drug treatment, a subset of10 animals from each group is killed. The epididymal white adiposetissue (EWAT), retroperitoneal (RP) fat, interscapular brown adiposetissue (IBAT) fat pads, and gastrocnemius muscle are removed, trimmed,and weighed. The percent body fat is estimated from the weight of theepididymal fat pad. A subset of five animals from each group is injectedip with 0.5 g/kg glucose. At 30 min postinjection, a plasma sample iscollected and analyzed for glucose content by the glucose oxidasemethod.

2. Treatment of Obesity in Humans

Formulations of diazoxide or derivatives prepared as described hereincan be tested for efficacy in obese humans. The study is conducted asdescribed by Alemzadeh (Alemzadeh, et al., J Clin Endocr Metab83:1911-1915 (1998)). Subjects consist of moderate-to-morbidly obeseadults with a body mass index (BMI) greater than or equal to 30 kg/m².Each subject undergoes a complete physical examination at the initialevaluation, body weight being measured on a standard electronic scaleand body composition by DEXA.

Before the initiation of the study, all subjects are placed on ahypocaloric diet for a lead-in period of 1 week. This is designed toexclude individuals who are unlikely to be compliant and to ensurestable body weight before treatment. Up to 50 patients are tested ateach dosage of drug. Daily dosage is set at 100, 200, and 300 mg/day.The daily dose is divided into 2 doses for administration. The dose isadministered as either one, two or three 50 mg capsules or tablets ateach time of administration. Individual patients are dosed daily for upto 12 months. Patients are reviewed weekly, weighed, and asked about anyside effects or concurrent illnesses.

Twenty-four-hour dietary recall is obtained from each patient. Thedietary recalls are analyzed using a standard computer software program.All patients are placed on a hypocaloric diet and encouraged toparticipate in regular exercise.

Before commencing, and after completion of the study, the followinglaboratory tests are obtained: blood pressure fasting plasma glucose,insulin, cholesterol, triglycerides, free fatty acids (FFA), andglycohemoglobin and measures of rate of appearance and oxidation ofplasma derived fatty acids. Additionally, routine chemistry profiles andfasting plasma glucose are obtained weekly to identify those subjectswith evidence of glucose intolerance and/or electrolyte abnormalities.Glucose is analyzed in plasma, by the glucose oxidase method.

Insulin concentration is determined by RIA using a double-antibody kit.Cholesterol and triglycerides concentrations are measured by anenzymatic method. Plama FFA is determined by an enzymatic colorimetricmethod. SI was assessed by an iv glucose tolerance test (IVGTT) usingthe modified minimal model. After an overnight fast, a glucose bolus(300 mg/kg) was administered iv, followed (20 min later) by a bolus ofinsulin. Blood for determination of glucose and insulin is obtained froma contra lateral vein at −30, −15, 0, 2, 3, 4, 5, 6, 8, 10, 19, 22, 25,30, 40, 50, 70, 100, 140, and 180 min. SI and glucose effectiveness (SG)are calculated using Bergman's modified minimal-model computer programbefore and after the completion of the study. Acute insulin response toglucose is determined over the first 19 min of the IVGTT, and theglucose disappearance rate (Kg) is determined from 8-19 min of theIVGTT. Body composition is measured by bioelectrical impedance beforeand at the completion of the study. Resting energy expenditure (REE) ismeasured by indirect calorimetry after an overnight 12-h fast, withsubjects lying supine for a period of 30 min. Urine is collected overthe corresponding 24 h, for measurement of total nitrogen anddetermination of substrate use, before and after the study.

3. Treatment of Obesity in Humans by Coadministering Diazoxide andPhentermine

Evaluation of a prolonged co-administration of solid oral dosage form ofdiazoxide or a derivative thereof and phentermine in obese humans with amoderate-to-morbidly and a body mass index (BMI) greater than or equalto 30 kg/m². Each subject undergoes a complete physical examination atthe initial evaluation, body weight being measured on a standardelectronic scale and body composition by DEXA.

Before the initiation of the study, all subjects are placed on ahypocaloric diet for a lead-in period of 1 week. This is designed toexclude individuals who are unlikely to be compliant and to ensurestable body weight before treatment. Up to 100 patients are tested.Daily dosage of diazoxide is set at 200 mg. The daily dose is dividedinto 2 doses for administration. The dose is administered as either a100 mg capsule or a 100 mg tablet at each time of administration.Individual patients are dosed daily for up to 12 months. Phentermine isadministered as a single daily dose of 15 mg. Patients are reviewedevery two weeks, weighed, and asked about any side effects or concurrentillnesses.

All patients are continued on a hypocaloric diet and encouraged toparticipate in regular exercise. Before commencing, and after completionof the study, laboratory tests as described in the example above areobtained.

4. Prevention of Diabetes in Prediabetic Humans

The example describes use of diazoxide in a prediabetic individual toprevent the occurrence of diabetes. Individuals included in the studyall have elevated risk of developing diabetes as measured by one of twomethods. In a fasting glucose assay they have plasma glucose valuesbetween 100 and 125 mg/dl indicating impaired fasting glucose, or in anoral glucose tolerance test they have plasma glucose values between 140and 199 mg/dl at 2 hours post-glucose load indicating they have impairedglucose tolerance. Treatment is initiated in any individual meetingeither criteria. Treated individuals receive either 200 mg diazoxide perday as a 100 mg capsule or tablet twice per day or as two 100 mgcapsules or tablets once per day. Placebo treated individuals receiveeither one placebo capsule or tablet twice per day or two placebocapsules or tablets once per day.

Treatment is continued for one year with OGTT or fasting glucosemeasured monthly.

5. A Sustained Release Coformulation of Diazoxide HCl and Metformin HClUse to Treat Diabetic Patients

A sustained release co-formulation of diazoxide HCl and metformin HCl isproduced by forming a compressed tablet matrix that includes 750 mg ofmetformin HCl and 100 mg of diazoxide HCl. These active ingredients areblended with sodium carboxymethyl cellulose (about 5% (w/w)),hypromellose (about 25% (w/w), and magnesium stearate (<2% (w/w)). Thecompressed tablet is further coated with a combination of ethylcellulose(80% (w/w)) and methyl cellulose (20% (w/w)) as a thin film to controlrate of hydration and drug release.

Type II diabetic patients are treated with the oral dosage form byadministration of two tablets once per day or one tablet every 12 hours.Treatment of the patient with the drug is continued until one of twotherapeutic endpoints is reached, or for so long as the patient derivestherapeutic benefit from administration. The two therapeutic endpointsthat would serve as the basis for the decision to cease treatmentinclude the patient reaching a Body Mass Index (BMI (kg/m²)) between 18and 25 or the re-establishment of normal glucose tolerance in theabsence of treatment. The patient is monitored periodically for (a)glucose tolerance using an oral glucose tolerance test, (b) glycemiccontrol using a standard blood glucose assay, (c) weight gain or loss,(d) progression of diabetic complications, and (e) adverse effectsassociated with the use of these active ingredients.

6. Prevention or Treatment of Weight Gain in a Patient Treated withOlanzapine

Pharmacotherapy for schizophrenia is initiated for a patient meeting DSMIII-R criteria for schizophrenia. The patient is administered 10 mg ofolanzapine (Zyprexa, Lilly) once per day. Adjunctive therapy to thepatient for schizophrenia includes 250 mg equivalent of valproic acid asdivalproex sodium (Depakote, Abbott Labs). Weight gain, dyslipidemia andimpaired glucose tolerance, and metabolic syndrome are high frequencyadverse events in patients treated with this combination ofanti-psychotics. Weight gain, dyslipidemia, impaired glucose toleranceor metabolic syndrome are treated by the co-administration of atherapeutically effective dose of a K_(ATP) channel opener. The patientis treated with administration of 200 mg/day of diazoxide as a oncedaily tablet formulation. Diazoxide administration continues until theweight gain, dyslipidemia, impaired glucose tolerance or metabolicsyndrome is corrected or until treatment of the patient with olanzapineis discontinued. Dyslipidemia is detected by measuring circulatingconcentrations of total, HDL, and LDL cholesterol, triglycerides andnon-esterified fatty acids. Impaired glucose tolerance is detectedthrough the use of oral or IV glucose tolerance tests. Metabolicsyndrome is detected by measuring its key risk factors including centralobesity, dyslipidemia, impaired glucose tolerance, and circulatingconcentrations of key proinflammatory cytokines.

Example 3: Clinical Study in Obese Pediatric and Adult PWS Patients

A single-center, open-label, single-arm clinical study (PC025) with adouble-blind, placebo-controlled, randomized withdrawal extension hasbeen carried out. Patients were initiated on a DCCR dose of about 1.5mg/kg (maximum starting dose of 145 mg) and were titrated every 14 daysto about 2.4 mg/kg, 3.3 mg/kg, and 4.2 mg/kg (maximum dose of 507.5 mg).These DCCR doses are equivalent to diazoxide doses of 1.03, 1.66, 2.28,and 2.9 mg/kg, respectively. Patients were up-titrated at each visit atthe discretion of the investigator. Any patient who showed an increasein resting energy expenditure and/or a reduction in hyperphagia fromBaseline through Day 27 or Day 55 was designated a Responder andeligible to be randomized in the double-blind phase. Everyone whocompleted the open-label phase was a Responder and was randomized in andcompleted the double-blind phase. During the double-blind,placebo-controlled, randomized withdrawal phase, Responders wererandomized in a 1:1 ratio either to continue on active treatment at thedose they were treated with on Day 55 or to the placebo equivalent ofthat dose for an additional 4 weeks (29 days). Non-responders continuedopen label treatment with DCCR at the dose they were treated with on Day55 for an additional 29 days. A total of 12 patients were enrolled inthe study.

Inclusion Criteria: Basic Requirements

-   -   Ability to follow verbal and written instructions with or        without assistance from caregiver    -   Informed consent form signed by the subject or their legal        guardian    -   Completed the screening process between 2 and 4 weeks prior to        Baseline Visit

General Demographic Characteristics

-   -   Male and female patients 10 to 22 years of age, inclusive at the        time of dosing    -   Genetically confirmed Prader-Willi syndrome    -   BMI exceeds the 95^(th) percentile of the age specific BMI value        on the CDC BMI charts or percent body fat≥35% (The body fat        criteria will only be used if there were a measurement made        within 12 months of the Screening Visit, and the patient has not        lost weight since the measurement. Under all other        circumstances, the BMI criteria will apply.)    -   Generally healthy as documented by the medical history, physical        examination, vital sign assessments, 12-lead electrocardiogram        (ECG), and clinical laboratory assessments

Specific Laboratory Test Results

-   -   fasting glucose≤126 mg/dL    -   HbA1c≤6.5%        Endpoints and Statistical Analysis

Every endpoint is measured in two timeframes: (1) during the open labeltreatment phase as change (or percent change) from Baseline to Day 69;and (2) during the double-blind, placebo-controlled, randomizedwithdrawal phase as change (or percent change) from Day 69 to Day 97.

Endpoints measured during the open label treatment phase were analyzedby paired t-test while those measured during the double-blind,placebo-controlled treatment phase are subjected to ANOVA and pairedt-tests.

Efficacy endpoints include: hyperphagia (measured using parent/caregiverresponses on a modified Dykens hyperphagia questionnaire—converted to anumeric score between 0 and 34); weight; body fat (measured by DEXA);lean body mass (measured by DEXA); resting energy expenditure (measuredby indirect calorimetry); respiratory quotient (measured by indirectcalorimetry); waist circumference; BMI; ghrelin; leptin; triglycerides;total cholesterol; HDL cholesterol; non-HDL cholesterol and LDLcholesterol. Additional information was collected in a behavioralquestionnaire. Tables 2 and 3 summarize the visits at which eachefficacy parameter was measured.

TABLE 2 Time points for assessment of efficacy parameters duringopen-label phase End of Open label Parameter Screening Baseline Visit 3Visit 4 Visit 5 Visit 6 treatment Hyperphagia + + + + + + + Body fatEither at screening + Lean body mass or baseline + Weight + + + + + + +REE & RQ + + + + Waist + + + + + + + circumference Ghrelin, leptin + +Lipids + + Behavioral + + questionnaire

TABLE 3 Time points for assessment of efficacy parameters duringdouble-blind treatment Day 69 Day 97 End of End of Open label doubleblind Parameter Screening Baseline treatment treatmentHyperphagia + + + + Body fat Either at screening or baseline + Leanbody + mass Weight + + + + REE & RQ + + + Waist + + + + circumferenceGhrelin, leptin + + Lipids + + + Behavioral + + questionnairePatients in the Study

Demographic information and relevant medical history for each patientare shown in Table 4. Eleven of the thirteen subjects enrolled inclinical study PC025 completed the open-label phase. All were identifiedas Responders and were, therefore, randomized in the double-blind phaseof the study. All subjects randomized in the double-blind phase of thestudy completed the phase.

Baseline characteristics of patients enrolled in the study are providedin Table 5.

TABLE 4 Demographic information and relevant medical history forpatients enrolled in PC025 PWS Age at GH Patient Sex Age sub-typediagnosis trt* Relevant medical history BN-01 M 11.6 Deletion 4 wk Noacanthosis nigricans, obesity @ 3 yr, asthma, undescended testes, fattyliver, sleep apnea CP-02 M 16.5 Deletion 3 wk Yes cerebral palsy,obesity @ 2 yr, type 2 diabetes, gynecomastia, undescended testicle,sleep apnea, asthma @ 1 yr TJ-03 M 18.6 Deletion 6 wk No obesity @ 3 yrwith hyperphagia, psychiatric illness @ 2 yr, undescended testicle,osteopenia AC-04 F 17.0 Deletion 15 yr No scoliosis, short stature,osteopenia MR-05 F 17.8 Deletion 5.7 yr No scoliosis, strabismus,amenorrhea SD-06 M 16.7 Deletion 3 yr Yes morbid obesity @ 6 yr, sleepapnea, scoliosis, pulmonary hypertension, undescended testes, strabismusAS-08 M 11.9 Deletion 10 wk Yes hyperphagia @ 3 yr, dyslipidemia,opthalmoplegia, osteopenia, scoliosis SP-09 F 21.6 Deletion 6 wk Noscoliosis, sleep apnea, osteopenia, amenorrhea DD-10 M 12.5 UPD 16 wkYes osteopenia SM-11 F 15.4 Deletion 1 wk Yes psychiatric disease,osteopenia, scoliosis AD-13 F 14.7 Deletion 4 wk No obesity @ 5 yr,osteopenia JG-15 M 14.4 Deletion 2 wk Yes obesity @ 5 yr NT-16 M 19.3Deletion 2 wk No Scoliosis, strabismus, sleep apnea

TABLE 5 Baseline characteristics of subjects who were randomized in thedouble-blind phase of clinical study PC025. Weight Height PercentHyperphagia REE Subject (kg) (cm) body fat BMI score % RDA RQ CP-02 97.2166 52.0 35.3 18.5 83% 0.86 AC-04 56.9 151 46.8 25.0 7 84% 0.78 MR-05113.1 145 59.1 53.8 20.5 83% 0.87 SD-06 133.6 145 53.5 51.5 3 102%  0.84AS-08 60.9 140 53.4 31.0 25.5 86% 1.03 SP-09 106.8 148 60.7 48.8 10.584% 0.72 DD-10 70.8 155 49.3 29.5 32 101%  0.97 SM-11 62.2 140 48.8 31.78 97% 0.81 AD-13 103.5 149 56.6 46.6 10 94% 0.85 JG-15 106.3 161 53.741.0 16 71% 0.79 NT-16 80.8 177 36.4 25.7 14 100%  0.78 Average 90.4152.5 51.8 38.2 14.95 89.6%  0.85Dosing

One subject, a treated type 2 diabetic, finished the open-labeltreatment period on a dose of 1.5 mg/kg. Of the remaining 10 subjects, 1finished the open-label treatment period at a dose of 2.4 mg/kg, and 3at 3.3 mg/kg. The last 6 subjects enrolled in the study finished theopen-label treatment phase at a dose 4.2 mg/kg.

Changes in Body Composition, Waist Circumference and Weight

Body fat and lean body mass were measured by DEXA at baseline and againat the end of the open label treatment. Since DEXA was not run on Day97, the only body composition measurements made on the subjectsrandomized in the double-blind phase occurred in the period fromBaseline to Day 69. The body composition changes are outlined in Table6. Changes in body composition by DEXA were evaluated separately forsubjects who were growth hormone treated and growth hormone naïve. Theseresults are shown in Table 6.

Weight by DEXA was calculated as the sum of body fat and lean body mass.The ratio of lean body mass to body fat was also calculated.

TABLE 6 Changes in body composition by DEXA from Baseline through Day 69Parameter n Percent Change p-value All subjects randomized in the doubleblind phase Body fat 11  −3.8% 0.011 Lean body mass 11  5.41% 0.001 Leanbody mass/fat mass ratio 11  9.82% 0.002 Weight 11  0.67% 0.150 Growthhormone treated subjects Body fat  6 −3.31% 0.056 Lean body mass  6 5.50% 0.005 Lean body mass/fat mass ratio  6  9.37% 0.014 Weight  6 0.90% 0.189 Growth hormone naïve subjects Body fat  5 −4.34% 0.083 Leanbody mass  5  5.30% 0.055 Lean body mass/fat mass ratio  5 10.36% 0.043Weight  5  0.39% 0.301

Treatment with DCCR for 10 weeks had a highly significant and clinicallyrelevant impact on body composition including reductions in body fat,increases in lean body mass and a very marked increase in lean body massto body fat ratio. Because these patients had almost equal lean bodymass and fat mass at Baseline, parallel increases in lean body mass andreductions in body fat result in almost no net change in weight. Ingeneral, the changes in body composition were of similar magnitude inboth growth hormone treated and growth hormone naïve subjects.

The changes in body composition were dose dependent. Those subjects whocompleted the open-label treatment phase at a dose of 4.2 mg/kgexperienced a 6.3% decrease in fat mass, a 9.2% increase in lean bodymass and a 16.6% increase in the lean body mass to fat mass ratio.

Three subjects in the study showed greater than 10% increase in leanbody mass. Every subject showed an increase in lean body mass/fat massratio. More than half of the subjects in the study showed a >10%increase in the lean body mass/fat mass ratio, and one showed more thana 20% increase.

FIGS. 1-4 summarize the percent change in body fat, lean body mass andlean body mass/fat mass ratio from Baseline through Day 69.

Weight and waist circumference were measured during the physical exam ateach visit. This data can be used to evaluate the change from Baselinethrough Day 69 for all subjects randomized in the double-blind phase, byarm for the period from Day 69 through Day 97 and in those who continuedon DCCR in the double-blind phase from Baseline through Day 97. Theresults from the period covering Baseline through Day 69 are summarizedin Table 7. The results from the period covering Day 69 through Day 97are shown in Table 8. The results for subjects who continued on DCCR inthe double blind phase from baseline through Day 97 are shown in Table9.

TABLE 7 Changes in weight and waist circumference from Baseline throughDay 69 Change/Percent Parameter n change p-value Weight 11 0.53% 0.317Waist circumference 11 −3.5 cm 0.003

TABLE 8 Changes in weight and waist circumference from Day 69 throughDay 97 Change/Percent p-value Parameter Arm n change comparing armsWeight DCCR 5 −1.7% 0.723 Weight Placebo 6 −1.1% Waist circumferenceDCCR 5 −2.9 cm 0.047 Waist circumference Placebo 5 0.25 cm

TABLE 9 Changes in weight and waist circumference from Baseline throughDay 97 for those treated with DCCR in the double-blind phase ChangeParameter n Through Day 97 p-value Weight 5 0.4% 0.828 Waist 5 −3.7 cm0.039 circumference

Interestingly, the change in weight from Baseline through day 69 by DEXAand by the standard weight measurement produces almost identical results(an increase of 0.67% by DEXA and 0.53% by the standard approach). Incontrast to the lack of change in weight, there was a statisticallysignificant reduction in waist circumference through Day 69 in allsubjects randomized in the double-blind phase; through Day 97 for thosewho continued on DCCR. The comparison of change in waist circumferencebetween arms between Day 69 and Day 97, during which the placebo treatedpatients showed an incremental increase in waist circumference, whilethose who continued on DCCR, showed a notable reduction. The reductionin waist circumference is consistent with the explanation that DCCRtreated subjects are losing visceral fat.

Changes in Hyperphagia

The hyperphagia questionnaire was administered at all visits. This datacan be used to evaluate the change from Baseline through Day 69 for allsubjects randomized in the double-blind phase, by arm for the periodfrom Day 69 through Day 97 and in those who continued on DCCR in thedouble-blind phase from Baseline through Day 97. The results from theperiod covering Baseline through Day 69 are summarized in Table 10. Theresults from the period covering Day 69 through Day 97 are shown inTable 11. The results for subjects who continued on DCCR in the doubleblind phase from baseline through Day 97 are shown in Table 12.

TABLE 10 Changes in hyperphagia from Baseline through Day 69 Parameter nPercent change p-value Hyperphagia 11 −31.6% 0.003

TABLE 11 Changes in hyperphagia from Day 69 through Day 97 p-valuecomparing Parameter Arm n Change arms Hyperphagia DCCR 5 2.0  0.389Hyperphagia Placebo 6 0.33

TABLE 12 Changes in hyperphagia from Baseline through Day 97 for thosetreated with DCCR in the double-blind phase Percent change Parameter nthrough Day 97 p-value Hyperphagia 5 −29.2% 0.006

There was a statistically significant reduction in hyperphagia in allsubjects randomized in the double-blind phase from Baseline through Day69 and in those who continued on DCCR through the double-blind phasefrom Baseline through Day 97.

DCCR treated patients at the end of 97 days of treatment showed animprovement in hyperphagia of 29.2% while those that were treated withDCCR for 69 days followed by 28 days of placebo treatment showed only a13.9% improvement in hyperphagia on Day 97. Thus, at the end of thedouble-blind phase, DCCR treated patients showed more than twice theimprovement in hyperphagia as did those who were randomized to placeboin the double-blind phase. Once patients discontinue from DCCRtreatment, given the long half-life of DCCR (28-32 hours) it takes about7-10 days to completely clear from circulation. Verbatim statements wereobtained from parents of subjects in the study suggesting that they hadseen their children's food related behavior deteriorate only in the lastcouple of weeks of the study, suggesting a longer double-blind phasemight have resulted in further separation of the arms. In general, themagnitude of impact on how upset subjects became when denied food, howeasy it was to get them to think about something else if once deniedfood, and the impact on the frequency of stealing food, digging throughthe trash for food and bargaining for food were of equivalent or greatermagnitude as the overall impact on the hyperphagia score. DCCR appearedto have lesser impact on how sneaky or quick subjects were with respectto food and on how often they got up at night to seek food.

Improvements in hyperphagia were observed in subjects with baselinehyperphagia ranging from 29 (−45%) to less than 5 (−33%) on a 0 to 34point scale.

About 25% of the subjects ended the open-label phase with very lowlevels of hyperphagia (2 or 3 on a 0 to 34 scale). These subjects tendedto be able to lose more body fat than the average. Two such subjects,both females, one growth hormone treated and one growth hormone naïve,lost more than 10% of their initial body fat mass through 10 weeks.

FIG. 1 shows the change in hyperphagia from Baseline through Day 69.

Changes in Lipids

A lipid panel was evaluated at Baseline, and again on Day 69 and Day 97.This data can be used to evaluate the change from Baseline through Day69 for all subjects randomized in the double-blind phase, by arm for theperiod from Day 69 through Day 97 and in those who continued on DCCR inthe double-blind phase from Baseline through Day 97. The results fromthe period covering Baseline through Day 69 are summarized in Table 13.The results for subjects who continued on DCCR in the double blind phasefrom baseline through Day 97 are shown in Table 14.

TABLE 13 Changes in Lipids from Baseline through Day 69 Parameter nPercent change p-value Total cholesterol 8  −4.0% 0.044 Triglycerides 7−21.0% 0.084 HDL-C 8  10.8% 0.244 LDL-C 8  −7.0% 0.030 Non-HDL-C 8 −6.5% 0.019

TABLE 14 Median Percent Change in lipids from Baseline through Day 97for those treated with DCCR in the double-blind phase Median Percentchange from Parameter Baseline through Day 97 Total Cholesterol −11.0%Triglycerides −41.8% HDL-C  25.2% LDL-C  −7.9% Non-HDL-C −13.4%

Consistent with previous studies involving DCCR, treatment of subjectsrandomized in the double-blind phase with DCCR from Baseline through Day69 resulted in a number of statistically significant changes in lipidsincluding reductions in total cholesterol, LDL cholesterol and non-HDLcholesterol. Even though the impact on triglycerides was of largermagnitude, it did not reach significance because of the smaller n andgreater variability in the population. In general, greater reductions intriglycerides were seen in those with significant elevations intriglycerides at Baseline. A similar pattern was observed in those whowere treated with DCCR through the end of the double-blind treatment.The decreases in total cholesterol, triglycerides, LDL-C and non-HDL-Cwere all larger in those who were treated with DCCR longer.

Changes in Leptin and Ghrelin

Leptin and ghrelin were measured at Baseline and again on Day 69. Theresults from Baseline through Day 69 for leptin and ghrelin are providedin Table 15.

TABLE 15 Leptin and ghrelin changes from Baseline through Day 69Parameter n Percent change p-value Leptin 6 −22.0% 0.061 Ghrelin 6−15.0% 0.052

Further evidence for loss of body fat comes from the analysis of leptin,the results of which are consistent with the DEXA data and the data onwaist circumference. Although not quite reaching statisticalsignificance, leptin is down more than 20% from Baseline.

While ghrelin may or may not contribute substantially to hyperphagia inPWS, reductions in ghrelin are beneficial in PWS patients.

Behavioral Changes

A questionnaire, adapted from the PWS natural history study, was used todocument the presence or absence of 23 PWS-associated behaviors atBaseline and again on Day 69. These behaviors generally fell into 4categories:

-   -   (1) aggressive, threatening and destructive behaviors;    -   (2) self-injurious behaviors;    -   (3) compulsive behaviors; and    -   (4) other behaviors.        The questionnaire was administered at Baseline and again on        Day 69. Discontinuation rates for aggressive, threatening,        destructive behaviors and for all other behaviors are shown in        Table 16.

TABLE 16 Discontinuation rates for various classes of behavior inclinical study PC025 Behaviors Discontinuation rate p-value Aggressive,threatening, destructive −62.5% 0.01 All other PWS associated behaviors−29.8%

The impact on aggressive, threatening and destructive behaviors wasindependent of an impact on hyperphagia.

Changes in Resting Energy Expenditure and Respiratory Quotient

The measurements for resting energy expenditure and respiratory quotientwere quite variable from visit to visit. Despite the variability,resting energy expenditure and respiratory quotient appeared to beunchanged from Baseline through Day 69.

Changes in Insulin Sensitivity

Treatment with DCCR in other clinical studies was associated withimprovements in insulin resistance as measured by changes in homeostaticmodel assessment of insulin resistance (HOMA-IR). Improvements ininsulin sensitivity are well documented in the literature on diazoxide.The subjects enrolled in the double-blind phase of this study were quiteinsulin sensitive at Baseline, which is typical of PWS patients in thisage range. Consistent with prior DCCR clinical studies and the historicdiazoxide literature, treatment with DCCR for 10 weeks resulted in animprovement in HOMA-IR from 2.61±1.85 at Baseline to 1.46±1.36 on Day69. The difference did not reach statistical significance (p=0.095).

Example 4: Clinical Studies with Smith-Magenis Syndrome Patients

In a first example, a Smith-Magenis syndrome patient is treated with anoral suspension of diazoxide. The initial dose is approximately 1 mg/kgadministered in divided doses. After the patient has been stably treatedwith 1 mg/kg for a period of 1 to 2 weeks, the dose is titrated to about1.5 mg/kg. After the patient had been stably treated with 1.5 mg/kg fora period of 1 to 2 weeks, the dose is titrated to about 2.0 mg/kg. Thisprocess of increasing the dose by about 0.5 mg/kg at each titration stepand the duration of treatment at each step of 1 to 2 weeks is continueduntil the patient displays an adequate response to treatment, or amaximal dose of 5 mg/kg is reached. Potential responses to treatmentcould include loss of body fat, reduction in hypotonia, an increase inthe lean body mass to fat mass ratio, reduction in hyperphagia,reduction in waist circumference, loss of weight, reduction in temperoutbursts and aggressive behavior, and improvements in cardiovascularrisk factors. Treatment with the drug is chronic and may continue forlife.

In a second example, a Smith-Magenis syndrome patient is treated with acontrolled release tablet formulation of diazoxide choline. The initialdose is approximately 1.5 mg/kg administered once daily. After thepatient has been stably treated with 1.5 mg/kg for a period of 1 to 2weeks, the dose is titrated to about 2.1 mg/kg. After the patient hasbeen stably treated with 2.1 mg/kg for a period of 1 to 2 weeks, thedose is titrated to about 2.7 mg/kg. This process of increasing the doseby about 0.6 mg/kg at each titration step and the duration of treatmentat each step of 1 to 2 weeks is continued until the patient displays anadequate response to treatment, or a maximal dose of 5 mg/kg is reached.Potential responses to treatment could include loss of body fat,reduction in hypotonia, an increase in the lean body mass to fat massratio, reduction in hyperphagia, reduction in waist circumference, lossof weight, reduction in temper outbursts and aggressive behavior andimprovements in cardiovascular risk factors. Treatment with the drug ischronic and may continue for life.

In a third example, a Smith-Magenis syndrome patient is treated with acontrolled release tablet formulation of diazoxide choline. The initialdose is approximately 1.5 mg/kg administered once daily. After thepatient has been stably treated with 1.5 mg/kg for a period of 1 to 2weeks, the dose is titrated to about 2.2 mg/kg. After the patient hasbeen stably treated with 2.2 mg/kg for a period of 1 to 2 weeks, thedose is titrated to about 2.9 mg/kg. This process of increasing the doseby about 0.7 mg/kg at each titration step and the duration of treatmentat each step of 1 to 2 weeks is continued until the patient displays anadequate response to treatment or a maximal dose of 5 mg/kg is reached.In parallel, the patient may also be treated with beloranib. Potentialresponses to treatment could include loss of body fat, reduction inhypotonia, an increase in the lean body mass to fat mass ratio,reduction in hyperphagia, reduction in waist circumference, loss ofweight, reduction in temper outbursts and aggressive behavior andimprovements in cardiovascular risk factors. Treatment with the drug ischronic and may continue for life.

In a fourth example, a Smith-Magenis syndrome patient is treated with acontrolled release tablet formulation of diazoxide choline. The initialdose is approximately 1.5 mg/kg administered once daily. After thepatient has been stably treated with 1.5 mg/kg for a period of 1 to 2weeks, the dose is titrated to about 2.3 mg/kg. After the patient hasbeen stably treated with 2.3 mg/kg for a period of 1 to 2 weeks, thedose is titrated to about 3.0 mg/kg. This process of increasing the doseby about 0.8 mg/kg at each titration step and the duration of treatmentat each step of 1 to 2 weeks is continued until the patient displays anadequate response to treatment, or a maximal dose of 5 mg/kg is reached.In parallel, the patient may also be treated with an unacylated ghrelinanalog. Potential responses to treatment could include loss of body fat,reduction in hypotonia, an increase in the lean body mass to fat massratio, reductions in hyperphagia, reductions in waist circumference,loss of weight, reductions in temper outbursts and aggressive behaviorand improvements in cardiovascular risk factors. Treatment with the drugwould be chronic and may continue for life.

In a fifth example, a Smith-Magenis syndrome patient is treated with acontrolled release tablet formulation of diazoxide choline. The initialdose is approximately 1.5 mg/kg administered once daily. After thepatient had been stably treated with 1.5 mg/kg for a period of 1 to 2weeks, the dose would be titrated to about 2.4 mg/kg. After the patienthas been stably treated with 2.4 mg/kg for a period of 1 to 2 weeks, thedose is titrated to about 3.3 mg/kg. This process of increasing the doseby about 0.9 mg/kg at each titration step and the duration of treatmentat each step of 1 to 2 weeks is continued until the patient displays anadequate response to treatment, or a maximal dose of 5 mg/kg wasreached. In parallel, the patient may also be treated with an MC4agonist. Potential responses to treatment could include loss of bodyfat, reduction in hypotonia, an increase in the lean body mass to fatmass ratio, reductions in hyperphagia, reductions in waistcircumference, loss of weight, reductions in temper outbursts andaggressive behavior and improvements in cardiovascular risk factors.Treatment with the drug would be chronic and may continue for life.

In a sixth example, a Smith-Magenis syndrome patient is treated with acontrolled release tablet formulation of diazoxide choline. The initialdose is approximately 1.5 mg/kg administered once daily. After thepatient had been stably treated with 1.5 mg/kg for a period of 1 to 2weeks, the dose is titrated to about 2.5 mg/kg. After the patient hasbeen stably treated with 2.5 mg/kg for a period of 1 to 2 weeks, thedose is titrated to about 3.5 mg/kg. This process of increasing the doseby about 1.0 mg/kg at each titration step and the duration of treatmentat each step of 1 to 2 weeks is continued until the patient displays anadequate response to treatment, or a maximal dose of 5 mg/kg wasreached. In parallel, the patient may also be treated with an MC4agonist. Potential responses to treatment could include loss of bodyfat, reduction in hypotonia, an increase in the lean body mass to fatmass ratio, reductions in hyperphagia, reductions in waistcircumference, loss of weight, reductions in temper outbursts andaggressive behavior and improvements in cardiovascular risk factors.Treatment with the drug would be chronic and may continue for life.

All patents and other references cited in the specification areindicative of the level of skill of those skilled in the art to whichthe invention pertains, and are incorporated by reference in theirentireties, including any tables and figures, to the same extent as ifeach reference had been incorporated by reference in its entiretyindividually.

One skilled in the art would readily appreciate that the presentinvention is well adapted to obtain the ends and advantages mentioned,as well as those inherent therein. The methods, variances, andcompositions described herein as presently representative of preferredembodiments are exemplary and are not intended as limitations on thescope. Changes therein and other uses will occur to those skilled in theart, which are encompassed within the spirit of the invention, aredefined by the scope of the claims.

Definitions provided herein are not intended to be limiting from themeaning commonly understood by one of skill in the art unless indicatedotherwise.

The inventions illustratively described herein may suitably be practicedin the absence of any element or elements, limitation or limitations,not specifically disclosed herein. Thus, for example, the terms“comprising”, “including,” containing”, etc. shall be read expansivelyand without limitation. Additionally, the terms and expressions employedherein have been used as terms of description and not of limitation, andthere is no intention in the use of such terms and expressions ofexcluding any equivalents of the features shown and described orportions thereof, but it is recognized that various modifications arepossible within the scope of the invention claimed. Thus, it should beunderstood that although the present invention has been specificallydisclosed by preferred embodiments and optional features, modificationand variation of the inventions embodied therein herein disclosed may beresorted to by those skilled in the art, and that such modifications andvariations are considered to be within the scope of this invention.

The invention has been described broadly and generically herein. Each ofthe narrower species and subgeneric groupings falling within the genericdisclosure also form part of the invention. This includes the genericdescription of the invention with a proviso or negative limitationremoving any subject matter from the genus, regardless of whether or notthe excised material is specifically recited herein.

Other embodiments are within the following claims. In addition, wherefeatures or aspects of the invention are described in terms of Markushgroups, those skilled in the art will recognize that the invention isalso thereby described in terms of any individual member or subgroup ofmembers of the Markush group.

What is claimed is:
 1. A method of increasing lower limb muscle mass of a subject having Smith-Magenis Syndrome (SMS), said method comprising administering to the subject a pharmaceutical formulation comprising an effective amount of a K_(ATP) channel opener, or a pharmaceutically acceptable salt thereof, and wherein the method does not comprise administering human growth hormone to the subject.
 2. The method of claim 1, wherein the K_(ATP) channel opener is diazoxide.
 3. The method of claim 1, wherein the pharmaceutically acceptable salt is diazoxide choline.
 4. The method of claim 1, wherein the pharmaceutical formulation further comprises at least one other active ingredient.
 5. The method of claim 1, wherein the pharmaceutical formulation comprises at least one excipient that affects the rate of release of the K_(ATP) channel opener or the pharmaceutically acceptable salt thereof.
 6. The method of claim 1, wherein the pharmaceutical formulation comprises at least one excipient that delays release of the K_(ATP) channel opener or the pharmaceutically acceptable salt thereof.
 7. The method of claim 1, wherein the pharmaceutical formulation is administered once per day.
 8. The method of claim 1, wherein the pharmaceutical formulation is administered twice per day.
 9. The method of claim 1, wherein the pharmaceutical formulation is administered for 1 or more years.
 10. The method of claim 1, wherein the diazoxide or a pharmaceutically acceptable salt thereof is administered orally.
 11. The method of claim 1, wherein the subject is an adult.
 12. The method of claim 1, wherein the subject is over the age of
 16. 